Polycyclic compounds

ABSTRACT

Compounds of Formula (I), methods for their preparation, pharmaceutical formulations and use thereof. ##STR1##

This application is a 371 of PCT/GB96/02945 filed Nov. 28, 1996.

BACKGROUND

The present invention relates to compounds which have been found toexhibit anti-acetylcholinesterase activity and/or inhibition of 5-HTuptake and/or inhibition of noradrenaline uptake. More specifically, theinvention concerns polycyclic compounds and analogues thereof, methodsfor their preparation, pharmaceutical formulations containing them andtheir use as neurotransmitter potentiating agents, in particular in thetreatment of symptoms of Alzheimer's disease.

Much work has been done in research in the area of drugs affectingneurotransmitter systems in the central nervous system (CNS).Neurotransmitter molecules are involved in rapid communication in thenormal CNS and in pathologic conditions of the CNS. Most of the drugsavailable to the psychiatrist or neurologist for the treatment of CNSdisease function by affecting neurotransmitter pathways directly orindirectly. Of all the CNS disorders known to date, those associatedwith organic or degenerative dementia are not able to be treatedeffectively with the range of drugs currently available. A particulardisorder, Alzheimer's disease, also known as degenerative dementia,senile dementia, senile dementia of the Alzheimer type and organic brainsyndrome, has no known effective treatment therefor.

Certain drugs, such as so-called centrally active muscarinic drugs (i.e.drugs which act directly on the acetylcholine receptors to produce aresponse), act on so-called muscarinic receptors. Muscarinic receptorshave been found to be made up of at least 3 subclasses: M₁, M₂ and M₃.These receptors are found in the brain, heart and gut, and as a result,the use of muscarinic drugs carries with it the possibility ofundesirable side effects such as nausea or slowing or stopping of theheart.

Tacrine, a tricyclic acetylcholine esterase inhibitor is known toproduce liver damage as a side effect, which, although not believed tobe irreversible in nature, is nevertheless undesirable.

There exists a need to provide more effective drugs for the treatmentof, or alleviation of symptoms of organic or degenerative dementiadiseases of the CNS.

SUMMARY OF INVENTION

It is an object of the invention to provide more effective and/orselective polycyclic drugs for the treatment of, or alleviation ofsymptoms of organic or degenerative dementia diseases of the CNS.

This and other objects of the invention will become apparent from thefollowing description and examples.

STATEMENT OF INVENTION

According to the present invention there is provided compounds ofgeneral Formula (I): ##STR2## wherein R¹ is selected from NH₂, OH, H, F,Cl, Br, I, OCH₃, C₁ -C₆ alkyl or aryl (phenyl);

R² is selected from H, Cl, Br, F, I, OH, C₁ -C₆ alkyl or C₁ -C₆ alkoxy;

R³ is selected from H, F, Cl, Br, I, OH, OCH₃ or C₁ -C₆ alkyl;

R⁴ is selected from H, F, Cl, Br, I, OH, OCH₃ or C₁ -C₆ alkyl;

R⁵ is selected from H, Br, F, Cl, I, NO, NR⁶ R⁷, (CH₂)₁₋₄ NR⁶ R⁷, OH, C₁-C₄ alkyl and C₁ -C₄ alkoxy;

R⁶ is selected from H and C₁ -C₄ alkyl;

R⁷ is selected from H and C₁ -C₄ alkyl;

X represents (CH₂), wherein n is a whole integer selected from 1, 2, 3or 4;

Y represents (CH)_(m) or (CH₂)_(m) wherein m is a whole integer selectedfrom 1, 2, or 3;

A represents C-- NHR⁹ wherein R⁹ is selected from H, C₁ -C₆ alkyl oraryl;

Ring B is a saturated or unsaturated carbon membered ring optionallyfused to Ring C at any face of Ring C which does not extend from acarbon of Ring D such that when Ring B is fused to Ring C, Ring C isoptionally substituted at unfused carbon atoms by one or more groupsindependently selected from H, C₁ -C₆ alkyl or --COOR⁸ wherein R⁸ isselected from H or C₁ -C₆ alkyl with the proviso that when Ring C is a 5or 6 carbon membered ring and is not fused to a ring B at least one ofR¹, R², R³ and R⁴ is not H.

Generic Formula (I) can be viewed as two further sub-generic Formulae(II) and (III). Formula (II) may be viewed as: ##STR3## wherein R⁵ isselected from H, F, Br, Cl, NO₂, NR⁶ R⁷, (CH₂)₁₋₄ NR⁶ R⁷, OH, C₁ -C₄alkyl and C₁ -C₄ alkoxy;

R⁶ is selected from H and C₁ -C₄ alkyl;

R⁷ is selected from H and C₁ -C₄ alkyl;

R¹, R², R³ and R⁴ are independently selected from H, F, Cl and OCH₃ ;

Ring B can be fused with any face of Ring C which does not extend from acarbon of Ring D;

Ring C is optionally substituted at unfused carbon atoms by one or moregroups independently selected from C₁ -C₆ alkyl or COOR⁸ wherein R⁸ is Hor C₁ -C₆ alkyl; and

X is (CH₂), wherein n is a whole integer selected from 1, 2 or 3.

Naturally the skilled addressee will appreciate that free acid additionsalts of compounds of Formula (I) and Formula (II) are encompassedwithin the present invention.

Suitable acid addition salts include those formed from hydrochloric,hydrobromic, nitric, perchloric, sulphuric, citric, tartaric,phosphoric, lactic, benzoic, glutamic, oxalic, aspartic, pyruvic,succinic, fumaric, maleic, oxaloacetic, isethionic, stearic, phthalic,methanesulphonic, p-toluene sulphonic, benzenesulphonic, lactobionic andglucuronic acids. Most preferably, the salts will be pharmaceuticallyacceptable.

Compounds of Formula (II) can also be viewed as subgeneric formulae(II(a)) ##STR4## and (II(b)) ##STR5## wherein R⁵ and X are as definedfor Formula (II), above.

Unless otherwise indicated, alkyl groups of R⁶, R⁷ and R⁸ in Formulae(I) and (II), may be straight or branched chain alkyl groups such asisopropyl, propyl, butyl, isobutyl, tertbutyl and the like.

Preferred compounds according to subgeneric Formula (II) on the basis oftheir activity include: ##STR6##

The anti-acetylcholinesterase and inhibition of noradrenaline and 5-HTuptake activity of compounds of general Formulae (I), (II), (II(a)) and(II(b)) has been demonstrated in a number of tests in vitro.

Particularly preferred compounds on the basis of their activity arecompounds (1), (2) and (7), and physiologically functional derivativesthereof.

According to a further embodiment of the present invention there isprovided a process for preparing compounds of general Formula (11(a)),which process comprises:

(A) Reacting anthranilonitrile (IV) with a benzosuberone (V). ##STR7##

Anthranonitrile (IV) may be substituted with halogen e.g. Cl, Br, F, andalkoxy groups e.g. methoxy group. Benzosuberone (V) comprises group Xwhich is --(CH₂)-- and m is a whole integer selected from 1, 2 and 3.Preferably, m is 2 or 3.

The benzosuberones (V) may be synthesised using substitutedbenzaldehydes (VI) and crotonic esters (VII) followed by reduction andcyclisation under reaction conditions employed in the art. An example ofsuch a scheme is depicted below. ##STR8##

Thus the benzosuberone (V) can be prepared, for example, using halogen(e.g. F, Cl, Br) substituted or alkoxy substituted (e.g. methoxysubstituted) benzaldehydes and crotonic esters followed by reduction andcyclisation reactions employed in the art as mentioned above.

To effect substitution at positions C₇, C₈, C₆, and C₅ of abenzosuberone the following strategies can be employed:

(i) For substitution in a 7 membered ring, the above synthesis can beadapted as follows: ##STR9## i.e. variations (alkyl) at C₉ may be madewherein R is selected from C₁ -C₆ alkyl, e.g. wherein R═CH₃.

(ii) Substitution at C₈ of benzosuberones can be made via one of twooptions: ##STR10## (iii) To effect substitution at C₇, a benzaldehyde isreacted with a substituted crotonate ester, such as ##STR11##

Thus, 5-benzosuberones are required in the above outlined processes.

In a still further embodiment of the invention there is provided aprocess for preparing compounds of Formula II(b), wherein R⁵ ═H##STR12## which process comprises: (A) Reaction of anthranilonitrile(IV) with isomeric 6-benzosuberones. 6-benzosuberones are made using C₁-C₆ alkoxy substituted (e.g. methoxy) or halogen substituted, C₁ -C₆alkyl substituted, nitro substituted or carboxy-α-Tetralones in a ringexpanding procedure as outlined hereinbelow: ##STR13##

Alternatively, certain molecules of Formula II may be synthesised in anumber of steps by first condensing a suitable alkyl formate ester, suchas an ethyl formate with an indanone, such as 1-indanone, and forming ahydroxymethylene indanone such as 2-hydroxymethylene-indan-1-one. Thisfirst condensation product can then be used in a further condensationreaction with a suitably substituted phenyl hydrazine hydrochloride,yielding a substituted pyrazole. Any substituents on the phenylhydrazine employed may be located at the ortho, meta or para positionsof the phenyl ring. Typically substituents are located in the paraposition. Suitable substituents which may be located on the phenyl ringinclude H, F, Cl, Br and OCH₃.

The substituted pyrazole can then be converted into a cyano-enamineusing a suitable alkali metal hydride, such as sodium hydride in anappropriate organic solvent, such as boiling O-xylene. The resultingcyano-enamine can then be subjected to Lewis acid catalysis to produce asubstituted molecule according to subgeneric formula (11(c)): ##STR14##

A reaction scheme illustrating the above outlined general procedure isshown below: ##STR15##

Naturally, the skilled addressee will appreciate that substituent R maybe selected from H, Cl, Br, F and OCH₃.

Thus, in a further variant of the present invention there is provided amethod for preparing a compound according to Formula (11(c)): ##STR16##wherein R is selected from H, F, Cl, Br and OCH₃ ; by

(i) condensing a 1-indanone with an alkyl formate forming a 2-OHmethylene indan-1-one;

(ii) condensing the 2-OH-methylene indan-l-one with a phenyl hydrazineof Formula VIII: ##STR17## wherein R is selected from H, F, Cl, Br, andOCH₃ ;

forming an indenopyrazole of Formula IX: ##STR18## (iii) opening thepyrazole ring and forming a phenyl amino cyano-1-indene of Formula X:##STR19## followed by Lewis base catalysis.

The skilled addressee will appreciate in step (i) that any base which iscapable of catalysing nucleophilic addition to a 1-indanone yielding atleast a 2-OH-methylene inden-1-one may be used in this step. Such basesgenerally have a pKa value of at least 16 and preferably more than 20.Such bases are generally soluble in aprotic solvents such as toluene(PhMe), tetrahydrofuran, diethyl ether, liquid NH₃, DMF, dimethoxyalkanes such as dimethoxy methane and dimethoxy ethane and the like.Suitable bases include alkali metal bases such as sodium or potassiumalkoxides such as potassium tertiary butoxide, sodium ethoxide, sodiummethoxide, sodium amide, KH, LiH, NaH, Lithium dialkyl amides such asLi-diazopropylamide, LiC(C₆ H₅)₃, KC(C₆ H₅)₃, and the like.

The alkyl formate may be any alkyl formate which is capable ofcondensation with the 1-indanone forming a 2-OH methylene inden-1-one.It is thought that the length of the alkyl arm may be of any lengthprovided that the end product of step (i) is a 2-OH-methyleneinden-l-one. For reasons of convenience the alkyl formate may be a C₁-C₁₀ alkyl formate, suitably a C₁ -C₆ alkyl formate or more suitably aC₁ -C₃ alkyl formate, such as ethyl formate.

In step (ii) the acidic species used in the reaction can correspond tothe salt of the phenyl hydrazine used. Examples of suitable acidicspecies include hydrochloric acid, nitric acid, sulphuric acid asappropriate. Generally, any acid used should be capable of acidcatalysed addition of phenyl hydrazine to 2-OH-methylene inden-1-oneforming an indenopyrazole of Formula (IX).

In step (iii), the base catalysed opening of the pyrazole ring of theindenopyrazole (IX), and subsequent formation of the phenyl aminocyano-1-indene (X) should be conducted in a solvent with a suitably highboiling temperature such that ring opening can occur. A suitable solventmay be an aprotic solvent having a boiling point above about 140° C.,such as O-xylene. The man skilled in the art will also appreciate thatany Lewis acid catalyst may be used in the Lewis acid catalysedre-arrangement so long as a phenyl amino cyano-1-indene of Formula (X)is converted into a compound of Formula (II(c)).

Carboxy-α-tetralones may or may not be substituted with C₁ -C₆ alkylgroups at position 2, 3 or 4.

Formula (III) may be viewed as: ##STR20## wherein R¹ is selected fromNH₂, OH, H, F, Cl, Br, I, OCH₃, C₁ -C₆ alkyl or aryl (phenyl);

R² is selected from H, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, Cl, Br, F, I, andOH;

R³ is selected from H, F, Cl, Br, I, OH, OCH₃ and C₁ -C₆ alkyl;

R⁴ is selected from H, F, Br, Cl, I, OCH₃, OH or C₁ -C₆ alkyl;

A represents C--NHR⁹ wherein R⁹ is selected from H, C₁ -C₆ alkyl oraryl;

X represents a carbon-carbon bond or represents --(CH₂)_(n) -- wherein nis a whole integer selected from 1, 2 or 3; and

a 5, 6, 7 or 8 carbon-membered unsubstituted ring can be optionallyfused to Ring C at any one of faces F, G or H indicated on Ring C, withthe proviso that when Ring C is a 5 or 6-carbon unsubstituted ring andis not fused at any of faces F, G and H at least one of R¹, R², R³ andR⁴ is not H.

Preferably, R¹ is selected from H, F. Cl, and CH₃ ;

R² is selected from H, Cl, F, Br, --OCH₃, NH, and CH₃ ;

R³ is selected from H, F, Cl, and CH₃ ;

R⁴ is selected from H, Cl, F, OH, and CH₃ ;

A represents C--NHR⁹ wherein R⁹ is selected from H and ##STR21## Xrepresents a carbon-carbon bond or represents --(CH₂)_(n) -- wherein nis 1; and a 6 membered carbon ring is optionally fused to Ring C at faceH, with the proviso that when Ring C is a 5 or 6-carbon-memberedunsubstituted ring and is not fused at any of faces F, G and H at leastone of R¹, R², R³ and R⁴ is not H.

Naturally the skilled addressee will appreciate that free acid additionsalts of compounds of Formula (III) are also encompassed within thepresent invention.

Suitable acid addition salts include those formed from hydrochloric,hydrobromic, nitric, perchloric, sulphuric, citric, tartaric,phosphoric, lactic, benzoic, glutamic, oxalic, aspartic, pyruvic,succinic, fumaric, maleic, oxaloacetic, isethionic, strearic, phthalic,methanesulphonic, p-toluene sulphonic, benzenesulphonic, lactobionic andglucuronic acids. Most preferably, the salts will be pharmaceuticallyacceptable.

Unless otherwise indicated, alkyl groups of R¹, R², R³ l R⁴ and R⁹present in Formula (III) may be straight or branched chain alkyl groupssuch as isopropyl, propyl, butyl, isobutyl, tertbutyl and the like.

Preferred compounds according to Formula III on the basis of theiractivity include: ##STR22##

The anti-acetylcholinesterase and inhibition of 5-HT uptake and/ornoradrenaline uptake activity of compounds of subgeneric Formula (III)has been demonstrated in a number of tests in vitro.

Particularly preferred compounds of subgeneric Formula (III) on thebasis of their activity are (8), (10), (14), (16) and (17), andphysiologically functional derivatives thereof.

According to a further embodiment of the present invention there isprovided a process for preparing compounds of general Formula (III)which process includes the, synthesis of an α-cyano ketone, such as theone depicted below: ##STR23##

In this case, the a- cyano ketone, cyclopentanone-2-carbonitrile wassynthesised by the Thorpe-Ziegler cyclisation of 1,4- dicyanobutane andsubsequent hydrolysis, as outlined above.

Substituted or unsubstituted aniline compounds can then be condensedwith cyano ketones according to the following general scheme and thenconverted to a tacrine derivative utilising Lewis acids: ##STR24##

Examples of Lewis acids which can be used in the above scheme includeBF₃.O(CH₂ CH₃)₂, AlCl₃ and TiCl₄. Examples of independently selectedsubstituents, R, which can be added forming aniline derivatives (A)include CH₃, OH, F, Br, Cl, and --OCH₃. Thus, there can be more than oneR substituent on the aniline derivative (A).

In a further alternative, the α-cyano ketone can be a six memberedα-cyano ketone which is also capable of being synthesised along similarlines as compound (B), thus: ##STR25## A fluoro-substituted aniline, inthis case a 4-fluoro-substituted aniline can be condensed with cyanoketone (C). ##STR26##

The resulting enamine is able to be cyclised to give a fluorinatedtacrine analogue, such as exemplified below: ##STR27##

In a further alternative, the a-cyano ketone can be a benzo substitutedderivative which can be synthesised along the following lines: ##STR28##

The α-cyano ketone can then be condensed with a substituted aniline, forexample a fluoro-substituted aniline, forming an enamine which can thenbe cyclised using a Lewis acid, such as TiCl₄.

The compounds of the present invention are indicated as being useful inalleviating symptoms of Alzheimer's disease. They may be employed intreating various forms of organic or degenerative dementia.

The invention thus further provides a method for the treatment ofAlzheimer's disease in humans, which comprises the administration of aclinically useful amount of a compound of Formula (I), (II) or (III) ora pharmaceutically acceptable salt or physiologically functionalderivative in a pharmaceutically useful form, once or several times aday or in any other appropriate schedule, orally, rectally, orparenterally.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of Formula (I), (II) or (III) or apharmaceutically acceptable salt or physiologically functionalderivative thereof for use in therapy, for example in the treatment ofAlzheimer's disease.

The amount of compound of Formula (I), (II) or (III) required to beeffective in a treatment for degenerative dementia, such as Alzheimer'sdisease will, of course, vary and is ultimately at the discretion of themedical or veterinary practitioner. The factors to be considered includethe condition being treated, the route of administration, and nature ofthe formulation, the mammal's body weight, surface area, age and generalcondition, and the particular compound to be administered. A suitableeffective dose lies in the range of about 0.01 to about 120 mg/kgbodyweight, e.g. 0.1 to about 120 mg/kg bodyweight, preferably in therange of about 0.1 to 50 mg/kg, for example 0.5 to 5 mg/kg. The totaldaily dose may be given as a single dose, multiple doses, e.g., two tosix times per day or by intravenous infusion for selected duration. Forexample, for a 75 kg mammal (e.g. a human) the dose range would be about8 to 9000 mg per day, and a typical dose could be about 50 mg per day.If discrete multiple doses are indicated treatment might typically be 15mg of a compound of Formula (I), (II) or (III) given up to 4 times perday.

Whilst it is possible for the active compound to be administered alone,it is preferable to present the active compound in a pharmaceuticalformulation. Formulations of the present invention, for medical use,comprise a compound of Formula (I), (II) or (III) or a salt thereoftogether with one or more pharmaceutically acceptable carriers andoptionally other therapeutic ingredients. The carrier(s) should bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of Formula (I), (II) or (III), or apharmaceutically acceptable salt or physiologically functionalderivative thereof together with a pharmaceutically acceptable carriertherefor.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of Formula(I), (II) or (III), or a pharmaceutically acceptable salt orphysiologically functional derivative thereof, and a pharmaceuticallyacceptable carrier therefor.

Formulations according to the present invention include those suitablefor oral, topical, rectal or parental (including subcutaneous,intramuscular and intravenous administration. Preferred formulations arethose suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredient. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a solution or suspension in an aqueous ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Mouldedtablets may be made by moulding in a suitable matching a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavourings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredients, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of Formula (I), (II) or(III), that is isotonic with the blood of the recipient.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of Formula (I), (II) or (III), which upondilution with an appropriate solvent give a solution for parenteraladministration as above.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavouring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

In a further aspect of the present invention provides the use of acompound of Formula (I), (II) or (III) or a pharmaceutically acceptablesalt or physiologically functional derivative thereof for themanufacture of a medicament for the treatment of degenerative braindisorders, such as Alzheimer's disease.

In a preferment there is provided use of a compound according to formula(I), (II) or (III) selected from compounds 1 to 18 as hereinabovedescribed and compound 29: ##STR29## or a pharmaceutically acceptablesalt or physiologically functional derivative thereof for themanufacture of a medicament for the treatment of degenerative braindisorders, such as Alzheimer's disease.

The invention will now be illustrated by the following non-limitingexamples.

Examples Section i(i): Illustration of the Synthesis of Compounds ofFormula II and Pharmacological Activity Thereof Equipment

Melting points were obtained on a Gallenkamp melting point apparatus inopen capillaries and are uncorrected.

¹ H NMR spectra were recorded on a Perkin-Elmer R32 spectrometeroperating at 90 MHz, on a Bruker SM250 spectrometer operating at 250.13MHz, and on a Bruker AMX400 spectrometer operating at 400.13 MHz, withthe WM250 and the AMX400 in Fourier Transform mode. J Values are givenin Hertz. ¹³ C spectra were recorded on a Bruker AMX400 operating at100.62 MHz in Fourier Transform mode.

Infrared spectra were recorded on a Unicam Mattson 1000 series FTIRspectrometer as thin films, Nujol mulls or in solution cells.

Flash column chromatography was carried out using CAMLAB Art. Nr81538 MNKieselgel 60 (0.040-0.063 mm) and Merck 7735 silica gel type 60(0.125-0.250 mm) or on modified C₁₈ :C₁ reverse phase silica gel^(R).Samples were applied in the solution or adsorbed onto silica.

Mass spectra were obtained on a AEIMST double-focusing massspectrometer, modified with a solid state console using a GEC 905computer based data system.

Carbon, hydrogen and nitrogen analysis were determined on a Carlo Erba1106 analyser using a technique based on the classical Pregl Dumasmethod.

Halogens were determined by combusting the sample in an oxygen flaskcontaining hydrogen peroxide and potassium hydroxide and titrating analcoholic solution of the products with mercuric nitrate usingdiphenylcarbazone as indicator (Mercurimetric method).

Sulphur was determined by combusting the sample in an oxygen flaskcontaining hydrogen peroxide and water and titrating an alcoholicsolution of the products with barium perchlorate using the mixedindicator THORON and methylene blue.

Toluene was dried over sodium; THF was pre-dried with anhydrous sodiumsulphate and distilled over calcium hydride or sodium benzophenoneketyl.

All solutions were dried over anhydrous sodium sulphate or anhydrousmagnesium sulphate and filtered.

Thin layer chromatography was carried out on plastic sheets precoatedwith 0.25 mm aluminium oxide also with fluorescent indicator UV₂₅₄, bothsupplied by CAMLAB.

General Procedure for the Cyclodehydration Reaction

2-amino-1-cyano-benzene, appropriate ketone (1.1 equivalents) andsodium-dried toluene (120 ml) were placed in a three-neckedround-bottomed flask fitted with an overhead stirrer. Boron trifluoridediethyl etherate (1.1 equivalents) was added slowly via syringe and thereaction mixture heated at reflux for 24 hours. On cooling, the toluenewas decanted and, to liberate the product, the remaining solids weretreated with sodium hydroxide (2M, 120 ml) and heated at reflux for 24hours. After cooling, the organic components were extracted withchloroform and the organic layers were combined, dried and the solventevaporated in vacuo to give the desired product.

In each case, the compounds made were easily identifiable by TLCanalysis where they showed as a characteristic near baseline spot(solvent; ethyl acetate).

In each case, a sample was recrystallised from the stated solvent foranalysis.

EXAMPLE 1 6-Amino-4, 5-benzo-[5H]-cyclopenta-[1,2-b]-quinoline (2)

2-amino-1-cyano-benzene (Aldrich Chemicals) (4.6 g, 38.9 mmol),2,3-dihydrobenzocyclopenten-[1H]-1-one (5.6 g, 42.4 mmol) (AldrichChemicals) and boron trifluoride diethyl etherate (1M, 5.3 ml, 43.3mmol) were treated according to the general procedure described hereinto give the title compound.

Recrystallised: m.p. (dec) 239-240° C. (EtOH). Found: C, 82.50; H, 5.2;N, 12.0; M⁺ 232, 1006. C₁₆ H₁₂ N₂ requires C, 82.7; H, 5.2; N, 12.1%;M⁺, 232.1000. δH(250 MHz, CD₃ OD) 3.78 (2H, s, CH₂,), 7.20-7.69 (5H, m,aryl-H), 7.94 (1H, d, J=8.5, aryl-H), 8.03 (1H, d, J=8.4, aryl-H),8.10-8.25 (1H, m, aryl-H). Maleate salt m.p. 212-214° C. Found: C, 68.6;H, 4.5; N, 7.9, C₁₆ H₁₂ N₂. C₄ H₄ O₄ requires C 68.95; H, 4.6; N, 8.05%.δH(250 MHz, DMSO-d₆) 3.91 (2H, s, CH₂), 2.60-4.70 (2H, br s, exchangeswith D₂ O, NH₂), 6.06 (2H, s, maleate), 7.50-8.00 (6H, m, aryl-H), 8.18(1H, d, J=7.2, aryl-H), 8.43 (1H, d, J=8.4, aryl-H), 8.71 (2H, br, s,exchanges with D₂ O, maleate).

EXAMPLE 2 7 Amino-5, 6-dihydro-benz-[c]-acridine (3)

2-amino-1-cyano-benzene (2.0 g, 16.9 mmol), α-tetralone (3,4-dihydro-[2H]-naphthalene-1-one) (Aldrich Chemicals) (2.7 g, 18.5 mmol)and boron trifluoride diethyl etherate (1M, 2.3 ml, 18.8 mmol) weretreated according to the general procedure described herein to give thetitle compound.

Recrystallised: m.p. 138-140° C. (EtOH). Found: C, 83.1; h, 5.8; n,11.3; M⁺, 246.1159. C₁₇ H₁₄ N₂ requires C, 82.9; H, 5.7; N, 11.3%; M⁺,246.1157. δH (90 MHZ, CDCl₃) 2.6-3.1 (4H, m, 2CH₂), 4.55 (2H, br s,exchanges with D₂ O, NH₂), 7.10-7.80 (6H, m, aryl-H), 8.00-8.20 (1H, m,aryl-H), 8.5-8.7 (1H, m, aryl-H). Maleate Salt m.p. 207-209° C. Found:C, 69.90; H, 4.8; N, 7.6; C₁₇ H₁₄ N₂. C₄ H₄ O₄ requires C, 69.6; H, 5.0;N, 7.7% δH (250 MHz, CD₃ OD) 2.7-3.2 (4H, m, CH₂), 6.22 (2H, S,maleate), 7.3-7.7 (4H, m, aryl-H), 7.87 (1H, t, J=7.3, aryl-H), 7.95-8.2(2H, m, aryl-H), 8.35 (1H, d, J=7.6, aryl-H).

EXAMPLE 3 7-Amino-5, 6-dihydro-4-methoxybenz-[c]-acridine (4)

2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 3,4-dihydro-5-methoxy-[2H)-napthalen-1-one) (Aldrich Chemicals) (8.1 g,46.0 mmol) and boron trifluoride diethyl etherate (1M, 5.7 ml, 46.6mmol) were treated according to general procedure described herein togive the title compound.

Recrystallised: m.p. 126-129° C. (CHCl₃). Found: C, 78.3; H, 5.65; N,10.0; M⁺, 276.1265. C₁₈ H₁₆ N₂ O requires C, 78.2; H, 5.8; N, 10.1%; M+,276.1263. δH (90 MHz, CDCl₃) 2.5-3.2 (4H, m, 2CH₂), 3.9 (3H, s, CH₃) ,4.6 (2H, br, s, exchanges with D₂ O, NH₂), 6.8-7.0 (1H, d, J=9, aryl-H),7.2-7.8 (2H, m, aryl-H), 8.0-8.35 (1H, m, aryl-H). Maleate salt m.p.(dec) 210-216° C. Found: C, 67.3; H, 5.0; N, 7.1; C₁₈ H₁₆ N₂ O. C₄ H₄,O₄requires C, 67.35; H, 5.1; N, 7.1%. δH (250 MHz, DMSO-d₆) 2.70-3.05 (4H,m, CH₂), 3.89 (3H, s, CH₂), 3.06 (2H, s, maleate), 7.29 (1H, d, J=8.1,aryl-H), 7.52 (1H, t, J=8.0, aryl-H), 7.64 (1H, t, J=7.3, aryl-H), 7.81(1H, d, J=7.8, aryl-H), 7.90 (1H, t, J=7.4, aryl-H), 7.13 (1H, d, J=8.3,aryl-H), 8.45 (1H, d, J=8.3, aryl-H), 8.57 (2H, br s, maleate).

EXAMPLE 4 7-Amino-5, 6-dihydro-3-chlorobenz-[c]-acridine (5)

2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 6-chloro-3,4-dihydro-[2H]-napthalen-1-one (Organon Laboratories) (8.8 g, 48.7 mmol)and boron trifluoride diethyl etherate (1M, 6.4 ml, 52.4 mmol) weretreated according to the general procedure described herein to give thetitle compound.

Recrystallised: m.p. 205-208° C. (EtOH). Found: C, 73.0; H, 4.6; N,10.3; M⁺, 280.0769. C₁₇ H₁₅ N₂ Cl requires C, 72.7; H, 4.7; N, 10.0%;M⁺, 280.0767 δH (90 MHz, CDCl₃) 2.7-3.1 (4H, m, 2CH₂), 4.6 (2H, br s,exchanges with D₂ O, NH₂), 7.1-8.2 (6H, m, aryl-H), 8.5 (1H, d, J=8.1,aryl-H). Maleate salt m.p. (dec.) 220-221° C. Found: C, 63.7; H, 4.05;N, 6.9; Cl, 9.1. C₁₇ H₁₅ N₂ Cl. C₄ H₄ O₄ requires C, 63.6; H, 4.3; N,7.05; Cl, 8.9%. δH (2.50 MHz, DMSO-d6) 2.30-3.06 (4H, m, 2CH₂), 3.34(2H, br s, NH₂), 6.05 (2H, s, maleate), 7.55-7.70 (3H, m, aryl-H), 7.88(1H, t, J=7.9, aryl-H), 8.07 (1H, d, J=8.5, aryl-H), 8.19 (1H, d, J=8.1,aryl-H), 8.43 (1H, d, J=8.3, aryl-H), 8.51 (2H, br s, maleate).

EXAMPLE 5 8-Amino-6, 7-dihydro-5H-benzo-[6, 7] cyclohepta [1, 2-b]quinoline (6)

2-amino-1-cyano-benzene (2.0 g, 16.9 mmol), 1-benzosuberone (6, 7, 8,9-tetrahydrobenzocyclohepten-5-one) (3.0 g, 18.7 mmol) and borontrifluoride diethyl etherate(1M, 2.6 ml, 18.7 mmol) were treatedaccording to the general procedure described herein to give the titlecompound.

Recrystallised: m.p. 190-192° C. (EtOH). Found: C, 83.5; H, 6.1; N,10.6; M⁺, 260.1304. C₁₈ H₁₆ N₂ requires C, 83.15; H, 6.2; N, 10.8%; M⁺,260.1313. δH (90 MHz-d6): 1.9-2.8 (6H, m, 3CH₃), 6.55 (2H, br s,exchanges with D₂ O, NH₂), 7.1-7.95 (7H, m, aryl-H), 8.2-8.35 (1H, m,aryl-H). Maleate salt m.p. 186-188° C. Found: C, 70.2; H, 5.4; N, 7.4C₁₈ H₁₆ N₂ C₄ H₄ O₄ requires C, 70.2; H, 5.35; N, 7.4% δH (250MHz, CD₃OD) 2.25 (2H, br s, CH₂), 2.63 (2H, br s, CH₂), 5.07 (2H, br s, CH₂),6.19 (2H, s, maleate), 7.35-8.05 (7H, m, aryl-H), 8.35 (1H, d, J=8.4,aryl-H).

EXAMPLE 6 13-Amino-1,2 dihydro-5-methoxy[1H] benz [7] annuleno [5,4-b]quinoline (1)

2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 6, 7, 8,9-tetrahydro-2-methoxy-5H-benzocyclohepten-5-one (synthesised accordingto the method of Khan A. M. et al., J. Chem Soc., (1966) p. 990) (8.7 g,45.8 mmol) and boron trifluoride diethyl etherate (1M, 6.2 ml, 50.7mmol) were treated according to the general procedure described hereinto give the title compound.

Recrystallised: m.p. 206-210° C. (EtOH). Found: C, 78.9; H, 6.4; N, 9.6;M⁺, 290.1419, C₁₉ H₁₈ N₂ O requires C, 78.60; H, 6.2; N, 9.6%; M⁺,290.1419. δH (90 MHz, DMSO-d6) 1.8-2.8 (6H, m, 3CH₂), 3.85 (3H, s, CH₃),6.5 (2H, br s, exchanges with D₂ O, NH₂), 6.75-8.4 (7H, m, aryl-H).Maleate salt m.p. 216-218° C. Found: C, 67.6; H, 5.2; N, 6.6. C₁₉ H₁₈,N₂O. C₄ H₄ O₄ requires C, 68.0; H, 5.45; N, 6.9%. δH (250 MHz, CD₃ OD)2.20-2.75 (6H, m, 3CH₃), 3.89 (3H, s, CH₃), 6.21 (2H, s, maleate),6.95-7.10 (2H, m, aryl-H), 7.60-7.72 (2H, m, aryl-H), 7.85-7.95 (2H, m,aryl-H), 8.35 (1H, d, J=8.7, aryl-H).

EXAMPLE 7 13-Amino 6.7 dihydro[1H] benz [7] annuleno [4,5-b]quinoline(7)

Anthranilonitrile (1.0 g, 8.5 mmol), 6, 7, 8,9-tetrahydro-5H-benzocyclo-hepten-6-one (El-Hossini M. S. et al.,Tetrahedron Lett., (1986) 27, p.3783) (1.5 g, 9.4 mmol) and borontrifluoride diethyl etherate (1M, 1.2 ml, 9.8 mmol) were treatedaccording to the general procedure (pg. 29) to give the title compound.

Recrystallised: m.p. 177-179° C. (CH₃ CH₂ OH). Found: C, 82.85; H, 6.4;N, 10.55; M⁺, 260.1315. C₁₈ H₁₆ N₂ requires C, 83.05; H, 6.2; N, 10.75%;M⁺, 260.1314. δH (250 MHz, CDCl₃) 2.08-2.68 (5H, m); 2.82-2.90 (1H, m);4.96 (2H, br s, exchanges with D₂ O, NH₂); 7.34-7.66 (6H, m, aryl-H),7.79 (1H, d, J=8.35, aryl-H), 7.00 (1H, d, J=8.43, aryl-H).

EXAMPLE 7(a) 1, 2, 3, 4-Tetrahydro-1-methylene-napthalene (IntermediateLeading to Compound 33)

N-Butyl lithium (Aldrich) (47 cm³, 74.8 mmol, 1.6 M solution in hexane)was added dropwise to a solution of methyl triphenylphosphonium iodide(Aldrich) (27.65 g, 68 mmol) in dry THF (150 cm³), under nitrogen at 0°C. α-Tetralone (Aldrich) (10 g, 68 mmol) in dry THF (100 cm³ was thenadded dropwise and the mixture stirred for 17 hours at room temperature.The reaction mixture was then added to water and extracted with ethylacetate. The combined extracts were then dried (Na₂ SO₄), filtered andconcentrated in vacuo. Purification was by column chromatography on aneutralised silica column (Et₃ N) (Eluant: Pet. Ether 40-60° C.)produced a colourless mobile oil.

δ_(H) (250 MHz, CDCl₃), 1.95 (2H, m, CH₂), 2.6 (2H, m, CH₂), 2.88 (2H,t, J 6.3 Hz, CH₂), 4.99 (1H, dd, J 1.4, 2.7 Hz, vinyl (C--H), 5.51 (1H,d, J 1.1 Hz, vinyl (C--H), 7.1-7.3 (3H, m, aryl), 7.65-7.7 (1H, m,aryl). νmax (LF)/cm⁻¹ 3085, 3066, 3028, 3017 (Ar-Hstr), 2990, 2937,2862, 2836 (C--H str), 1627 (C═C str).

EXAMPLE 7(b) 5, 7. 8, 9-Tetrahydro-[6H]-benzocyclohepten-6-one(Intermediate Leading to Compound 33)

1, 2, 3, 4-Tetrahydro-1-methylene-naphthalene (Example 1(a)) (1 g, 6.934mmol) in THF (22 cm³) was added to a vigorously stirring solution ofsilver nitrate (2.356 g, 13.87 mmol), water (26 cm³) and methanol (26cm³). This was followed by immediate addition of iodine (1.76 g, 6.9mmol). After stirring for 1 hour, precipitated silver iodide was removedby filtration and the liquors concentrated in vacuo. Purification was bycolumn chromatography (Eluent: 15% ethyl acetate/N-hexane) and Kugelrohrdistillation produced a mobile yellow oil (75° C., 0.05 mmHg).

Found : C, 81.81; H, 7.55% Calc. for C₁₁ H₁₂ O: C, 82.46; H, 7.55% δ_(H)(250 MHz, CDCl₃) 2.00 (2H, quin, J 6.6 Hz, 4-H), 2.58 (2H, t, J 6.9 Hz,5-H), 2.96 (2H, t, J 6.3 Hz, 3H), 3.63 (2H, s, 1-H), 7.05-7.3 (4H, m,aryl). νmax (LF)/cm⁻¹ : 3064, 3019 (Ar--H str), 2936, 2862 (Aliph C--Hstr), 1708 (C═Ostr).

EXAMPLE 7(c) 13-Amino-6, 7-dihydro [1H] benz [7] annuleno [4, 5-b]quinoline (7) and 13-amino 1, 2-dihydro [1H] benz [7] annuleno [2, 3-b]quinoline (33)

Boron trifluoride diethyl etherate (1M, 0.89 g, 0.78 cm³, 6.24 mmol) wasadded to a stirring solution of 5, 7, 8,9-tetrahydro-[6H]-benzocyclohepten-6-one (Example 1(a) (ii)) (1.0 g,6.24 mmol) anthranilonitrile (0.67 g, 5.67 mmol) and dry toluene (50cm³) and then heated under reflux for 19 hours. After cooling, thetoluene was decanted and 2M NaOH (50 cm³) was added and heated underreflux for 18 hours. After cooling, the reaction mixture was extractedwith dichloromethane. The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo to afford a brown solid.Purification was by column chromatography [Eluant: dichloromethane:ethanol: ammonia (200:8:1)] afforded two products. Kugelrohrdistillation of the first fraction (180° C., 0.01 mmHg) produced anoff-white solid (7). The second component was also distilled (225° C.,0.01 mmHg) to give a colourless solid (33).

(i) Compound 7: m.p. 187-188° C. Found : C, 82.9; H. 6.1; N, 10.85% C₁₈H₁₆ N₂ requires: C, 83.05; H, 6.2; N. 10.8% δH [250 MHz, (CD₃)SO] 2.08(2H, m, 6-H), 2.34 (2H, m, 7-H) , 2.63 (2H, m, 5-H), 6.23 (2H, br s,NH₂), 7.25-7.45 (4H, m, aryl), 7.54 (1H, dd, J 2.6, 9.8 Hz, aryl), 7.60(1H, dd, J 1.2, 7.4 Hz, aryl), 7.77 (1H, dd, J 0.9, 8.4 Hz, aryl), 8.27(1H, d, J 8.3 Hz, aryl). νmax (NUJOL)/cm⁻¹ : 3469, 3295 (N--H str),3092, 3054 (Ar--H str), 1642, 1566, 1498, 1430 (C═C str).

(ii) Compound 33: m.p. 250-252° C. (dec.). ##STR30## Found :C, 83.1; H,6.1; N, 10.8% C₁₈ H₁₆ N₂ requires C, 83.05; H, 6.2; N, 10.2% δ_(H) [250MHz, (CD₃)SO] 2.93 (2H, t, J 6.5 Hz, 10-H), 3.22 (2H, t, J 6.5 Hz,11-H), 4.34 (2H, s, 5-H), 6.40 (2H, br s, NH,), 7.05-7.35 (5H, m, aryl),7.49 (1H, dd, J 7.0, 8.1 Hz, aryl), 7.68 (1H, d, J 8.4 Hz, aryl), 8.14(1H, d, J 8.4 Hz, aryl). νmax (NUJOL)/cm⁻¹ : 3480, 3311 (N--H str), 3168(Ar--H str), 1647, 1573 (C═C str).

EXAMPLE 8 Pharmacology

Four assays were employed to measure biological activity:

Inhibition of Acetylcholinesterase uptake activity (AChE)

Inhibition of Butyrylcholinesterase activity (BChE)

Inhibition of 5-HT (serotonin) uptake.

Inhibition of noradrenaline uptake (NA).

The biological activity of primary interest was that of AChE and 5-HTuptake. BChE uptake was measured such that compounds selective for AChEcould be located. Inhibition of noradrenaline uptake was measured sincecompounds having the ability to potentiate transmission involvingnoradrenaline as well as 5-HT and acetylcholine are of interest.

EXAMPLE 8(A) Anti-acetylcholinesterase Assay

The anticholinesterase assay is based on the method of Ellman et al.,(Biochem. Pharmac. (1961) 7 pp88-95) by measuring the activity of AChEin the following coupled reactions: ##STR31## Absorption max is at 324nm. (i) Enzyme Source for AChE

The following method of isolating the enzyme is essentially amodification of the method of Rotundo R. L. (1984) J. Biol. Chem 259(21) pp. 13186-13194. 5 Male Rats (Sprague Dawley) weighing approx 250 gwere killed by CO₂ overdose and cervical dislocation.

The brain was removed and homogenised (9 strokes at 840 rpm with 4volumes of phosphate buffer pH 7.4+10 mM (EDTA) and centrifuged at27,000 g for 30 minutes.

The supernatant was discarded and the pellet resuspended in phosphatebuffer with 10 mM EDTA+1- Triton X100 (2 ml/g wet weight). The crudehomogenate was centrifuged at 27,000 g for 30-40 minutes.

The pellet was discarded and the supernatant was dispensed into 0.5 mlaliquots and stored at -20° C. until required.

Phosphate Buffer (0.1M. pH 7.4)

Na₂ HPO₄ -5.75 g

NaH₂ PO₄ 2H₂ O-1.48 g

Made up to 500 ml with distilled H₂ O, pH 7.4.

Acetylthiocholine-5.2 mM (3.07 mg/2 ml phosphate buffer)

PDS-21 mM

(ii) Assay Procedure

0.5 ml aliquots of brain (enzyme solution) as prepared above were thawedout. 2 ml of phosphate buffer was added to each aliquot. 2 ml of theenzyme solution was incubated with 2 ml PDS for 60 minutes at 0° C. Thecomposition of blank, control and test solutions are given below:

Blank

0.9 ml phosphate buffer (0.1 M, pH 7.4)

0.1 ml enzyme, PDS soln

Control

0.85 ml phosphate buffer (0.1M, pH 7.4)

0.1 ml enzyme, PDS soln

0.05 ml acetylthiocholine (5.2 mM)

Presence of Inhibitor

0.8 ml phosphate buffer (0.1M, pH 7.4)

0.1 ml enzyme, PDS soln

0.05 ml Acetylthiocholine 5.2 mM

0.05 ml inhibitor (Examples 1-7) to give final concentrations of 1, 3,10, 30, 100, 300 nM; 1, 3, 10, 30, 100 μM.

Change in absorbance was measured at 30 second intervals for 3 minutesat 324 mm. The control was taken as 100%. Inhibitor was calculated as apercentage of the control. A graph of Log of inhibitor conc. versus %control was plotted and IC₅. values calculated by interpolation. Resultsare shown in Table I.

EXAMPLE 8(B) Anti-butyrylcholinesterase Assay

The anticholinesterase assay is based on measuring the activity of BChEin the following coupled reactions: ##STR32## (i) Enzyme Source: BChE(Sigma product c-7512) 2.5 mg/ml phosphate buffer with 1% Triton X100was made fresh for each experiment. The following components wereutilised:

Phosphate Buffer (0.1M, pH 7.4)

Na₂ HPO₄ 5.75 g

NaH₂ PO₄ 2H₂ O 1.48 g

Made up to 500 ml with distilled H₂ O, pH 7.4

Acetylthiocholine 5.2 mM (3.07 mg/2 ml phosphate buffer)

PDS 21 mM (2.31 mg in 1 ml CH₃ CH₂ OH, plus 4 ml phosphate buffer)

(ii) Assay Procedure

1 ml of enzyme solution (i), was incubated with 2 ml PDS for 60 minutesat 0° C.

Components of the assay blank, controls and test solutions are providedbelow:

Blank

0.9 ml phosphate buffer (0.1M, pH 7.4)

0.1 ml enzyme PDS soln

Control

0.85 ml phosphate buffer (0.1 M, pH 7.4)

0.1 ml enzyme, PDS soln

0.05 ml Acetylthiocholine (5.2 mM)

Presence of Inhibitor

0.8 ml phosphate buffer (0.1M, pH 7.4)

0.1 ml enzyme PDS soln

0.05 ml Acetylthiocholine (5.2 mM)

0.05 ml inhibitor (Examples 1-7) to give final concentrations of 1, 3,10, 30, 100, 300 nM; 1, 10, 30, 100μM.

Change in absorbance was measured at 30 second intervals at 324 nm.Control was taken as 100%. Inhibitor was calculated as a percentage ofcontrol. A graph of Log of inhibitor conc. versus % control was plottedand IC₅₀ values calculated by interpolation.

Results are shown in Table I.

EXAMPLE 8(C) Monoamine Uptake Inhibition Assay

(i) Synaptosomal Preparation

One male rat (Sprague Dawley) weighing approx. 200-250 g was sacrificedby cervical dislocation. The brain was dissected out and the cerebellumdiscarded. The brain was then weighed and 10 ml ice cold sucrose (0.32M)added per gram tissue. The brain was then homogenised with a Teflonpestle (clearance 0.16 mm) at 840 rpm for 8 up-and-down strokes and thencentrifuged at 100 g for 10 minutes at 4° C. The pellet was discardedand the supernatant retained (crude synaptosomal preparation).

(ii) Monoamine Uptake Inhibition Assay (5-HT and NA)

The assay was based on a method as described by Snyder and Coyle (1969)J. Pharm. Exp. Ther. 165, 78-86 and Horn et al (1973) J. Neurochem 21,pp 883-888.

Control

2 ml Krebs buffer

Non-Specific Uptake

5-HT-determined by 10 μM fluoxetine (2 ml) (Eli Lilly Limited).NA-determined by 1 μM desipramine (2 ml) (Sigma Chemical Co.)

Presence of Inhibitor

Various concentrations of inhibitor(i.e. from Examples 1-7) to be tested(1, 3, 10, 30, 100, 300 nM; 1, 3, 10, 30, 100 μM) for uptake inhibitionof monoamines (2 ml).

Krebs Henseleit Buffer

To make 1 liter:

    ______________________________________                                        NaCl            6.92   g        118.9                                                                              mM                                       KCl             0.35   g        4.69 mM                                       MgSO.sub.4 7H.sub.2 O                                                                         0.29   g        1.18 mM                                       CaCl.sub.2      1.25   ml       1.25 mM                                       KH.sub.2 PO.sub.4                                                                             0.16   g        1.17 mM                                       NaHCO.sub.3     2.1    g        24.99                                                                              mM                                       Glucose         2.0    g        11.1 mM                                       Ascorbic Acid   0.2    g        1.1  mM                                       EDTA            0.05   g        0.13 mM                                       Nialamide       3.279  mg       12.5 μg                                    ______________________________________                                    

All tubes were set up in triplicate. 2 ml of Krebs buffer (above),non-specific uptake inhibitor or drug (i.e. Examples 1-7) to be testedwas incubated in a shaking water bath at 37° C. 100 μl of the preparedsynaptosomal preparation was added to each tube and incubated for 5minutes in a shaking water bath at 37° C. Any reaction was stopped byplunging the tubes into an ice water bath. ³ H NA (10⁻⁷ M) or ³ H 5-HT(10³¹ 7 M) was added to each tube and incubated for 5 minutes in ashaking water bath at 37° C. Any reaction was stopped by plunging thetubes into an ice-water bath. Accumulated monoamines were collectedusing a Brandell Cell Harvester under mild vacuum. Filters were rinsed(2×) using 4 ml of ice-cold 0.9% saline. Scintillation fluid was added(4 ml/tube). Radioactivity was measured on a scintillation counter.

Non-specific values were subtracted from total values. The control wastaken as 100%. Drug effects were calculated as a percentage of controlinhibitor value. A graph of log of drug concentration versus % controlwas plotted and IC₅₀ values were calculated by interpolation.

Results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                     IC50#μM(±SEM, n = 5)                                                    5HT   NA                                                         COMPOUND  FORM     UPTAKE      AChE   BChE                                    ______________________________________                                        (1)       BASE     0.7     3.6   68.8   % C72                                                                  (4.2)  AT                                                                            100                                                                           μM                                           SALT     0.02    1.8   17.4   34.4                                                                   (0.094)                                                                              (6.7)                                 (2)       SALT     2.2     2.3   0.35   3.1                                                                    (0.059)                                                                              (0.40)                                (3)       BASE     4.6     12.1  37.4   3.3                                                                    (2.9)  (0.056)                                         SALT     2.0     13.2  7.8    3.8                                                                    (0.6)  (0.60)                                (4)       BASE     5.8     1.4   47.5   10.3                                                                   (2.9)  (0.70)                                          SALT     2.1     12.2  17.1   1.9                                                                    (0.99) (0.15)                                (5)       BASE     14.3    4.1   144.1  NO                                                                     (7.3)  BLOCK                                                                         AT                                                                            100                                             SALT     5.2     6.1   17.93  7.1                                                                    (1.4)  (8.2)                                 (6)       BASE     4.7     ND    328.5  36.0                                                                   (53.7) (9.0)                                           SALT     1.0     1.9   17.5   4.0                                                                    (0.38) (0.57)                                (7)       BASE     0.02    ND    38.2   26.4                                                                   (8.1)  (0.44)                                ______________________________________                                    

Examples Section 1(ii): Illustration of the Synthesis of Compounds ofFormula (11(c)) via Alternative Route EXAMPLE 1(ii) (a)2-Hydroxymethylene-indan-1-one (Intermediate Leading to Compound 2)

1-Indanone (Aldrich) (5.0 g, 37.8 mmol) in toluene (25 cm³) was addeddropwise, to a stirring solution of sodium hydride (Aldrich) (1.8 g,45.4 mmol 60% w/w dispersion in oil), ethyl formate (Aldrich) (5.6 g,75.6 mmol) and toluene (50 cm³), under nitrogen, at 0° C. The reactionwas stirred for 17 hours before adding water (50 cm³). The organic layerwas washed with water and 2M NaOH. The combined aqueous extracts wereacidified with 10 M HCl and the precipitate extracted withdichloromethane. The combined organic extracts were dried (Na₂ SO₄),filtered and concentrated in vacuo to afford a yellow-orange solid. Ananalytically pure sample was obtained by Kugelrohr distillation (0.01mmHg/100° C.) to give a yellow solid m.p. 110-112° C.

Found C, 74.9; H, 4.9% Calc. for C₁₀ H₈ O₂ : C, 75.0; H, 5.0% δ_(H) (270MHz, CDCl₃) 3.62 (2H, s, CH₂ -3), 7.31-7.65 (3H, m, aryl), 7.66 (1H, s,CH₂ -2), 7.84 (1H, d, J 7.8 Hz, Ar-H-7), 11.71 (1H, br s, OH). νmax(NUJOL)/cm⁻¹ : 3050 (Ar--H str), 2621 (Aliph-H str and enol of 1,2-dicarbonyl), 1694, 1682, 1621, 1614, 1567, 1574, 1556, 1531, 1519,1538, 1504 (C═O str and C═C str).

EXAMPLE 1(ii) (b) 1-Phenyl-1, 4-dihydro-indeno[1,2-c] pyrazole(Intermediate Leading to Compound 2)

2-Hydroxymethlene indan-1-one (Example 1(ii)(a) (6.0 g, 37.5 mmol),phenylhydrazine hydrochloride (Aldrich) (5.48 g, 37.9 mmol), 10 Mhydrochloric acid (1 cm³) and ethanol (30 cm³) were stirred under refluxfor 19 hours. After cooling, the solvent was evaporated under reducedpressure and the residue dissolved in dichloromethane, then washed with2M sodium hydroxide. The organic layer was separated, dried (Na₂ SO₄)filtered and concentrated in vacuo. Purification by Kugelrohrdistillation afforded an off-white solid (150° C., 0.01 mmHg) m.p.119-120° C.

Found : C, 82.5; H, 5.1; N, 12.0% C₁₆ H₁₂ N₂ requires : C, 82.7; H, 5.2;N, 12.1% δ_(H) (250 MHz, CDCl₃) 3.67 (2H, s, 4-H), 7.25-7.80 (9H, m,aryl), 7.68 (1H, s, CH-3). νmax (NUJOL)/cm⁻¹ : 3104, 3059 (Ar--H str),2799, 2724, 2676, 2619 (Al--H str).

EXAMPLE 1(ii)(c) 1-Phenylamino-2-cyano-1-indene (Intermediate Leading toCompound 2)

1-Phenyl-1, 4-dihydro-indeno [1, 2-c) pyrazole (Example 1(ii)(b) (5.95g, 25.6 mmol) sodium hydride (4.096 g, 102.4 mmol; 60% w/w dispersion inoil) and O-xylene (20 cm³) were heated under reflux under nitrogen for 3hours. After cooling, water was added and the mixture made neutral bythe addition of hydrochloric acid. All organic matter was extracted withdichloromethane, then dried (Na₂ SO₄), filtered and concentrated invacuo. Purification was by column chromatography [Eluant:dichloromethane: ethanol (100:5)] followed by Kugelrohr distillation(155° C.; 0.01 mmHg) afforded an off-white solid, m.p. 151-153° C.

Found : C, 82.5; H, 5.2; N, 12.15% C₁₆ H₁₂ N₂ requires : C, 82.7; H,5.2; N. 12.1% δ_(H) (250 MHz, CDCl₃) 3.68 (2H, s, 3-H), 6.69 (1H, br s,NH), 7.18-7.51 (9H, m, aryl). νmax (NUJOL)/cm⁻¹ : 3300 (N--H str), 3128,3061, 3042 (Ar--H str), 2177 (C.tbd.N str), 1615, 1596, 1573, 1538 (C═Cstr).

EXAMPLE 1(ii)(d) 6-Amino-4,5-benzo-[5H]-cyclopenta-[1, 2b]-quinoline(Compound 2)

Under nitrogen, titanium tetrachloride (6.3 g, 3.7 cm³, 33.15 mmol) wasadded to 1-phenylamino-2-cyano-1-indene (Example 1(ii) (c) (7.0 g; 30.14mmol) and stirred at 140-150° C. for 11/2 hours. After cooling, 10M NaOH(15 cm³) was added and the whole was heated under reflux for 11/2 hours.The cooled reaction mixture was then filtered and the residue washedwith dichloromethane. The solid residue was further extracted usingsoxhlet apparatus (ethanol). The combined organic extracts wereconcentrated in vacuo to afford a dark solid. Purification by was columnchromatography [Eluant: dichloromethane: ethanol: NH₃ (150:8:1)]followed by Kugelrohr distillation (220° C.; 0.05 mmHg) afforded anoff-white solid, m.p. 250° (dec.)

Found : C, 82.5; H, 5.4; N, 12.3% C₁₆ H₁₂ N₂ requires : C, 82.7; H, 5.2;N, 12.1% δ_(H) [250 MHz, (CD₃)₂ SO] 3.86 (2H, s, CH,), 7.09 (2H, br s,NH₂), 7.41-7.50 (3H, m, aryl), 7.64-7.68 (2H, m, aryl), 7.93 (1H, dd, J1.0, 8.5 Hz, aryl) 8.09 (1H, m, aryl) 8.29 (1H, dd, J 1.0 & 8.4 Hz,aryl). νmax (NUJOL)/cm⁻¹ : 3446, 3306 (N--H str), 3138, 3060, 3026(Ar--H str), 1653, 1618, 1606, 1579, 1567, 1508 (C═C str).

EXAMPLE 1(ii) (e) 1-(4-Fluorophenyl)-1, 4-dihydro-indeno [1, 2-c]pyrazole (Intermediate Leading to Compound 34)

2-Hydroxymethylene indan-1-one, (Example 1(ii) (a) (4.004 g; 250 mmol),p-fluorophenyl hydrazine hydrochloride (Aldrich) (4.106 g; 25.25 mmol)10M hydrochloric acid (1 cm³) and ethanol (30 cm³), were heated underreflux for 19 hours. After cooling, the solvent was evaporated underreduced pressure, then taken up in dichloromethane and washed with 2MNaOH. The organic layer was separated, dried (Na₂ SO₄), filtered andconcentrated in vacuo. Purification by Kugelrohr distillation (140° C.;0.01 mmHg) afforded a yellow solid, m.p. 104-105° C.

Found : C, 76.5; H, 4.5; N, 11.3% M⁺, 250.0880 C₁₆ H₁₁ FN₂ requires : C,76.8; H, 4.4; N, 11.2% M, 250.096 δ_(H) (250 MHz, CDCl₃) 3.65 (2H, s,4-H), 7.20-7.31 (4H, m, aryl), 7.44 (1H, m, aryl), 7.53 (1H, m, aryl),7.65 (1H, s, 3-H), 7.66-7.72 (2H, m, aryl). νmax (NUJOL)/cm⁻¹ : 3113,3088, 3058, 3004 (Ar--H str), 1539, 1515 (C═C str), 1215 (C--F str).

EXAMPLE 1(ii)(f) 1-(4-Fluorophenyl)-2-cyano-1-indene (IntermediateLeading to Compound 34)

1-(4-Fluorophenyl)-1, 4-dihydro-indeno [1, 2-c] pyrazole (Example 1(ii)(e) (4.0 g; 15.98 mmol) sodium hydride (2.56 g; 63.92 mmol; 60% w.wdispersion in oil) and O-xylene (15 cm³) were heated under reflux, undernitrogen, for 3 hours. After cooling, water was added and the mixturemade neutral by the addition of hydrochloric acid. All organic materialwas extracted with dichloromethane and the combined extracts dried (Na₂SO₄) filtered and concentrated in vacuo. Purification was by columnchromatography (Eluant: dichloromethane] gave the product and startingmaterial, m.p. 172° C. (dec.) b.p. 155° C./0.01 mmHg.

Found : C, 76.5; H, 4.5; N, 11.2%; M⁺, 250.0889 C₁₆ H₁₁ FN₂ requires :C, 76.8; H, 4.4; N, 11.2%; M, 250.0906. δ_(H) [250 MHz, (CD₃)₂ SO] 3.65(2H, s, CH₂ -3), 7.15-7.35 (4H, m, aryl), 7.40-7.55 (3H, m, aryl), 7.88(1H, m, aryl), 9.22 (1H, br S, NH). νmax (NUJOL)/cm⁻¹ : 3340, 3302 (N--Hstr), 3142, 3078, 3064 (Ar--H str), 2179 (C.tbd.N str), 1218 (C--F str).

EXAMPLE 1(ii)(g) 6-Amino-8-Fluoro-4, 5-benzo-[5H]-cyclopenta-[1,2-b]-quinoline (34)

Under nitrogen to 1- (4-fluorophenyl) -2-cyano-1-indene (Example1(ii)(f)) (1.0 g; 4.0 mmol) was added titanium tetrachloride (0.83 g;0.48 cm³ ; 4.4 mmol). The reaction mixture was then stirred at 140-150°C. for 11/2 hours before cooling and adding 10 M NaOH (10 cm³), thenheating under reflux for a further 1 hour. The cooled reaction mixturewas filtered and the residue washed with dichloromethane. The solidresidue was further extracted using soxhlet apparatus for 17 hours(ethanol). The combined organic extracts were dried (Na₂ SO₄), filteredand concentrated in vacuo to afford a dark solid. Purification was bycolumn chromatography [Eluant: Dichloromethane: Ethanol: ammonia(100:8:1)] followed by Kugelrohr distillation (220° C.; 0.02 mmHg) gavethe title compound, m.p. 250° C. (dec.).

Found : C, 76.55; H, 4.4; N, 11.4%; M⁺, 250.0904 C₁₆ H₁₁ FN₂ requires :C, 76.8; H, 4.4; N, 11.2%; M, 250.0906 δ_(H) [(250 MHz, (CD₃)₂ SO] 3.84(2H, s, CH₂), 6.81 (2H, br s, NH₂), 7.43-7.54 (3H, m, aryl), 7.65 (1H,m, aryl), 7.95 (1H, dd, J 5.8 9.2 Hz, aryl), 8.01 (1H, m, aryl), 8.08(1H, dd, J 2.8, 11.0 Hz, aryl). νmax (NUJOL)/cm⁻¹ : 3484, 3316, 3270(N--H str), 3185 (Ar--H str), 1190 (C--F str).

EXAMPLE 1(ii)(h) 1-(4'-Chlorophenyl)-1, 4-dihydro-indeno [1, 2-c]pyrazole (Intermediate Leading to Compound 35)

2-Hydroxymethyl inden-1-one (Example 1(ii)(a) (4.0 g; 25.00 mmol),p-chlorophenylhydrazine hydrochloride (Aldrich) (4.52 g; 25.25 mmol),10M hydrochloric acid (1 cm³) and ethanol (30 cm³) were heated underreflux for 22 hours. After cooling, the solvent was evaporated and theresidual dissolved in dichloromethane and washed with 2M sodiumhydroxide. The organic extracts were then dried (Na₂ SO₄), filtered andconcentrated in vacuo. Purification was by column chromatography(Eluant: dichloromethane] and recrystallisation (ethanol) gave off-whiteneedle shaped crystals, m.p. 128-129° C.; b.p. 185° C.; 0.05 mmHg.

Found : C, 72.2; H, 4.0; Cl, 13.7; N, 10.2% M⁺ 268.0587, 266.0562 C₁₆H₁₁ ClN₂ requires : C, 72.05; H, 4.2; Cl, 13.3; N, 10.5% M 268.0581,266.0611 δ_(H) (250 MHz, CDCl₃) 3.66 (2H, s, 4-H), 7.25-7.46 (2H, m,aryl), 7.47-7.67 (4H, m, aryl), 7.69-7.72 (3H, m, aryl & 3-H). νmax(NUJOL)/cm⁻¹ : 3110, 3085, 3054, 3044 (Ar--H str), 1533, 1506, 1487 (C═Cstr), 759 (C--Cl str).

EXAMPLE 1(ii)(i) 1(4-Chlorophenyl)-2-cyano-1-indene (IntermediateLeading to Compound 35)

Under nitrogen 1-(4'-chlorophenyl)-1, 4-dihydro-indeno [1, 2-c] pyrazole(Example 1(ii) (h) (3.0 g, 11.2 mmol), sodium hydride (1.80 g; 45 mmol;60% dispersion in oil) and O-xylene (10 cm³) and oxylene, were heatedunder reflux for 16 hours). After cooling, water was added and themixture made neutral by the addition of hydrochloric acid. All organicmaterial was extracted with dichloromethane then dried (Na₂ SO₄),filtered and concentrated in vacuo to afford a dark solid. Purificationwas by column chromatography (Eluant: dichloromethane) and Kugelrohrdistillation [210° C.; 0.05 mmHg] produced the product, m.p. 125-126° C.

Found : C, 72.0; H, 4.0; N, 10.3%; M⁺, 268.0600, 266.0508 C₁₆ H₁₁ ClN₂requires : C, 72.05; H, 4.2; N, 10.5%; M, 268.0581, 266.0611 δ_(H) [(250MHz, (CD₃)SO] 3.70 (2H, s, 4-H), 7.23-7.26 (2H, m, aryl), 7.28-7.57 (5H,m, aryl), 7.83-7.95 (1H, m, aryl), 9.33 (1H, br s, NH). νmax(NUJOL)/cm⁻¹ : 3306 (N--H str), 3191, 3110, 3044 (Ar--H str), 2185(C.tbd.N str), 759 (C--Cl str).

EXAMPLE 1(ii)(j) 6-Amino-8-chloro-4, 5-benzo-[5H]-cyclopenta-[1,2-b]-quinoline (35)

Under nitrogen, titanium tetrachloride (0.65 g; 0.38 cm³ ; 3.44 mmol),was added to 1-(4'-chlorophenyl) -2-cyano-1-indene (Example 1(ii)(i)(0.835 g; 3.13 mmol) and heated under reflux for 11/2 hours. Aftercooling, 10M NaOH (10 cm³) was added and heated under reflux for 11/2hours. After cooling the reaction was filtered and the residue washedwith dichloromethane. The solid residue was further extracted usingsoxhlet apparatus (ethanol). The combined organic extracts wereconcentrated in vacuo to afford a dark solid. Purification was by columnchromatography [Eluant: dichloromethane: ethanol: ammonia (200:8:1) andKugelrohr distillation (250° C.; 0.05 mmHg) gave a brown solid, m.p.247-249° C. (decomp.).

Found : C, 72.0; H, 4.2; Cl, 13.4; N, 10.55% M⁺, 268.0605, 266.0639 C₁₆H₁₁ ClN₂ requires: C, 72.05; H, 4.2; Cl, 13.3; N, 10.5% M, 268.0581,266.0611 δ_(H) [(250 MHz, (CD₃)2SO] 3.84 (2H, s, CH₂), 6.92 (2H, br s,NH₂), 7.42-7.51 (2H, m, aryl), 7.59 (1H, dd, J 2.3, 9.0 Hz, aryl),7.63-770 (1H, m, aryl), 7.89 (1H, d, J 9.0 Hz, aryl), 7.97-8.04 (1H, m,aryl), 8.39 (1H, d, J 2.3, Hz, aryl). νmax (NUJOL)/cm⁻¹ : 3457, 3308(N--H str), 3194, 3059, 3011 (Ar--H str), 761 (C--Cl str).

EXAMPLE 1(ii)(k) 1-(4'-Methoxyphenyl)-1,4-dihydro-indeno[1,2-c] pyrazole(Intermediate Leading to Compound 36)

2-Hydroxymethylene inden-l-one (Example 1(ii) (a) (4.0 g; 25 mmol),p-methoxyphenyl hydrazine hydrochloride (Aldrich) (4.41 g; 25.25 mmol),10 M hydrochloric acid (1 cm³) and ethanol (30 cm³), were heated underreflux, for 21 hours. After cooling, the mixture was concentrated invacuo and the residue dissolved in dichloromethane, then washed with 2MNaOH, dried, filtered and concentrated in vacuo. Purification by columnchromatography [Eluant: (dichloromethane: ethanol: ammonia (200:8:1)]Kugelrohr distillation (170° C.; 0.02 mmHg) and recrystallisation(ethanol) afforded needle shaped crystals, m.p. 102-103° C.

Found: C, 77.60; H, 5.5; N, 10.9%; M⁺, 262.1062 C₁₇ H₁₄ N₂ O requires :C, 77.8; H, 5.4; N, 10.7%; M, 262.1106 δ_(H) (250 MHz, CDCl₃) 3.65 (2H,s, 4-H), 3.90 (3H, s, O--CH₃), 7.04-7.10 (2H, m, aryl), 7.23-7.30 (2H,m, aryl), 7.45 (1H, m, aryl), 7.53 (1H, m, aryl), 7.60-7.66 (3H, m, aryl& 3-H). νmax (NUJOL)/cm⁻¹ : 3107, 3072, 3049, 3005 (Ar--H str), 1537,1518, 1498 (C═C str).

EXAMPLE 1(ii) (l) 1-(4'-Methoxyphenyl)-2-cyano-1-indene (IntermediateLeading to Compound 36)

Under nitrogen, 1-(4'-methoxyphenyl)-1, 4-dihydro-indeno [1, 2-c]pyrazole (Example 1(ii)(k) (3.0 g; 11.44 mmol), sodium hydride (Aldrich)(1.1 g; 27.5 mmol; 60% dispersed in oil) and o-xylene (10 cm³), wereheated under reflux for 16 hours. After cooling, water was added and themixture made neutral by the addition of 2M HCl. All organics wereextracted with dichloromethane, then dried (Na₂ SO₄), filtered andconcentrated in vacuo to afford a dark solid. Purification was by columnchromatography [Eluant: dichloromethane: ethanol: ammonia (150:8:1)],followed by Kugelrohr distillation (205° C.; 0.05 mmHg) gave acolourless crystalline solid, m.p. 178-180° C.

Found : C, 77.8; H, 5.6; N, 10.8%, M+, 262.1132 C₁₇ H₁₄ N₂ O requires :C, 77.8; H, 5.4; N, 10.7%, M, 262.1106 δ_(H) (250 MHz, CDCl₃) 3.65 (2H,s, CH₂ -3), 3.84 (3H, s, O-CH₃), 6.52 (1H, br s, NH), 6.93 (2H, d, J 8.8Hz, Ar-H-2' & H-6'), 7.21 (2H, d, J 8.8 Hz, Ar--H-3' & H-5'), 7.30 (1H,d, J 7.0 Hz, aryl), 7.37 (1H, dd, J 1.1 & 8.9 Hz, aryl), 7.43 (1H, dd, J1.0, 7.0 Hz, aryl), 7.48 (1H, d, J 7.3 Hz, aryl). νmax (NUJOL)/cm⁻¹ :3377 (N--H str), 3100, 3074, 3039 (Ar--H str), 2186 (C.tbd.N str).

EXAMPLE 1(ii)(m) 6-Amino-8-methoxy-4,5-benzo-[5H]-cyclopenta-[1,2-b]-quinoline (36)

Under nitrogen, titanium tetrachloride (0.80 g; 0.46 cm³ ; 4.2 mmol) wasadded to 1-(4'-methoxyphenyl)-2-cyano-1-indene (Example 1(ii)(1)) (1.0g; 3.81 mmol) and heated under reflux for 3 hours. After cooling, 10MNaOH (15 cm³) was added and heated under reflux for 1 hour. Aftercooling, the reaction was filtered and the residue washed withdichloromethane. The solid residue was further extracted using soxhletapparatus (ethanol). The combined organic extracts were concentrated invacuo and purified by column chromatography [Eluant: dichloromethane:ethanol: ammonia (100:8:1)] and Kugelrohr distillation (250° C.; 0.05mmHg) to give a yellow solid, m.p. 234° C. (decomp.).

Found : C, 78.0; H, 5.3; N, 10.6%; M⁺, 262.1102 C₁₇ H₁₄ N₂ O requires :C, 77.8; H, 5.4; N, 10.7%; M, 262.1106 δ_(H) [(250 MHz, (CD₃),SO] 3.83(2H, s, 5-H), 3.90 (3H, s, O--CH₃, 7.26 (1H, dd, J 2.7, 9.1 Hz, 9-H),7.39-7.47 (2H, m, 2-H & 3-H), 7.62-7.66 (2H, m & d, J 2.6 Hz, aryl &7-H), 7.82 (1H, d, J 9.1 Hz, 10-H), 7.95-8.02 (1H, m, aryl). νmax(NUJOL)/cm⁻¹ : 3426, 3325, 3273 (N--H str), 3163, 3051 (Ar--H str),1660, 1608, 1563, 1521 (C═C str).

Examples Section 2: Illustration of the Synthesis of Compounds ofFormula III and Pharmacological Activity Thereof EXAMPLE 9(A) Ethyl1-Anilino-1-cyclopentene-2-carboxylate

A mixture of aniline (6.0 g, 64.5 mmol), ethylcyclopentanone-2-carboxylate (Aldrich Chemicals) (10.0 g, 64.1 mmol) andcalcium chloride (7.6 g, 68.5 mmol) in THF (100 ml) was heated underreflux for 24 hours. After being allowed to cool, the suspension wasfiltered and the solvent was removed from the filtrate under reducedpressure. Kugelrohr distillation of the residue (125° C., 0.02 mmHg)gave the title product as a pale yellow liquid.

(Found: C, 72.5; H, 7.4; N, 5.95, Calc. for C₁₄ H₁₇ NO₂ : C, 72.7; H,7.4; N, 6.1%. δH (250 MHz; CDCl₃) 1.32 (3H, t, J=7.1, CH₃ CH₂ O), 1.87,(2H, quin, J=7.4, CH₂ CH₂ CH₂), 5.28 (2H, t, J=7.2, CH₂ CCO₂ R), 2.80(2H, t, J=7.5, CH₂ CNHPh), 4.22 (2H, q, J=7.1, CH₃ CH₂ O), 7.00 -7.35(5H, m Ar--H), 9.64 (1H, Br s, NH) m/z 231 (M⁺ -7Et, 17%)

EXAMPLE 9(B) 12-Oxo-2,3,5,12-tetrahydro-β-quinindene

The above ester (Example 9(A)) (8.0 g, 34.6 mmol) was added dropwise tovigorously boiling biphenyl (32.0 g) and the mixture was left heatingunder reflux for 15 minutes and then allowed to cool. The biphenyl wasremoved by washing with dichloromethane and the resulting slurryfiltered to give an off-white powder. Subsequent recrystallisation fromethanol gave the title compound as off-white crystals.

(Found: C, 77.8; H, 5.8; N, 7.4. Calc. for C₁₂ H₁₇ NO: C, 77.8; H, 6.0;N, 7.6%. δH[250 MHz, (CH₃)₂ SO] 2.03 (2H, quin, J=7 .5, CH₂ CHCH₂, 2.69(2H, t, J=7.3, CH₂ CCO), 2.98 (2H, t, J=7.8, CH₂ CNH), 7.26 (1H, tt,J=6.8 and 1.2, 8 or 9 Ar--H). 7.47 (1H, d, J=7.6, 7 or 10 Ar--H), 7.58(1H, tt, J=6.8 and 1.5, 8 or 9 Ar--H), 8.08 (1H, dd, J=8.1 and 1.3, 7 or10 Ar-H), 11.91 (1H, br s, N--H).

EXAMPLE 9(C) 9-Chloro-2,3-dihydro-1H-cyclopenta [1,2-b] quinoline

The above quinoline (Example 9(B)) (3.6 g, 19.5 mmol) was heated underreflux with phosphorous oxychloride (20 ml, 215 mmol) for 1.5 hours.This was poured on to ice and gradually made alkaline with ammonia.

The precipitated solids were filtered and washed with copious amounts ofwater. The remaining solids were purified by Kugelrohr distillation (75°C., 0.1 mmHg) to give the title compound as a white powder.

(Found: C, 70.7; H, 5.0; N, 6.7; Cl, 17.5. Calc. for C₁₂ H₁₀ ClN: C,70.8; H, 4.95; N, 6.9; Cl, 17.4%). δH (250 MHz); CDCl₃) 2.24 (2H quin,J=7.6, CH₂ CH₂ CH₂), 3.16 (2H, t, J=7.5, CH₂ CH₂ CH₂), 3.24 (2H, t,J=7.7, CH₂ CH2CH₂), 7.57 (1H, td, J=6.9 and 1.3, 8 or 9 Ar--H), 7.68(1H, td, J=6.9, and 1.5, 8 or 9 Ar--H), 8.04 (1H, dd, J=8.4 and 0.7, 7or 10 Ar--H), 8.15 (1H, dd, J=8.3 and 1.3, 7 or 10 ArH).

EXAMPLE 9(D) N-(Phenylmethyl)-9-amino-2,3-dihydro-1H-cyclopenta[1,2-b]quinoline (28)

Chloroquinoline derivative (Example 9(C)) (2.0 g, 9.8 mmol), benzylamine(1.2 g, 11.2 mmol) and phenol (4.0 g, 42.6 mmol) were heated at 180° C.for 3 hours. After cooling, 5M sodium hydroxide (50 cm³) was added andthe organic components were extracted into dichloromethane, dried (Na₂SO₄), filtered and the solvent was evaporated. Any remaining volatileswere removed by distillation and the residue was dissolved in hotethanol, decolorised (charcoal) and recrystallised to give an off-whitepowder.

m.p. 173-174° C. (Found: C, 82.95; H, 6.5; N. 10.2;. C₁₉ H₁₈ N₂ requiresC, 83.2; H, 6.6; N, 10.2%). δH (250 MHz; CDCl₃) 2.08 (2H, quin. J=7.5,CH₂ -2), 3.04 (2H, t, J=7.8, CH₂ -1), 3.17 (2H, t, J=7.2, CH₂ -3) 4.80(2H, d, J=6.1, CH₂ Ph), 5.02 (1H, br s, NH), 7.27-7.40 (6H, m, Ph--H andAr--H-7), 7.57 (1H, ddd, J=8.3, 6.9 and 1.3, Ar--H 8), 7.94 (1H, dd,J=8.4 and 1.2, Ar--H-5). M/Z 274.147 (M⁺, 95%).

EXAMPLE 10 2-Amino-cyclopent-1-ene-carbonitrile. (Intermediate leadingto (22)

1, 4-Dicyanobutane (Aldrich Chemicals) (21. 6 g, 0. 2 mmol) sodiumhydride (60% oil dispersion; 8.0 g, 0.2 mmol) and T.H.F. (100 ml) wereheated under reflux for 16 hours. After cooling to 0° C., water (100 ml)was added and the upper layer was separated, dried (Na₂ SO₄), filteredand the solvent evaporated. Recrystallisation from hot (80° C.) toluenegave the product.

m.p. 14514 146° C. (Found: C, 6.6; H, 7.77; N, 26.05. calc. for C₆ H₈ N₂C, 66.6; H, 7.5; N, 25.9%). δH[250 MHz, (CD₃)₂ SO] 1.76 (1H, quin,J=7.4, CH₂ -4), 2.33 (1H, t, J=7.9, CH₂ -3), 2.37 (1H, t, J=7.1, CH₂-5), 6.36 (1H, br s, NH₂).

EXAMPLE 11 2-Oxo-cyclopentane-carbonitrile (Intermediate leading to(22))

Cyano-enamine (Example 10) (2.7 g, 25 mmol) and 1M-hydrochloric acid (30ml) were stirred at room temperature for 4 hours. The solution wassaturated with ammonium chloride and the organic components wereextracted into dimethyl ether, dried (Na₂ SO₄), filtered and the etherwas evaporated. Kugelrohr distillation (100° C., 1 mmHg) gave theproduct as a colourless liquid. (Found: C, 65.3; H, 6.3; N, 12.7. calc.for C₆ H₇ NO C, 66.0; H, 6.5; N, 6.5; N, 12.8%) max (liquid film) /cm⁻¹3004 and 2902 (C--H), 2264 (CN) and 1779 (C═O). δH (400 MHZ; CDCl₃)1.81-2.47 (6H, m, CH₂), 3.17 (1H, ddd, J=10.9, 8.5 and 0.6, CH-1).

EXAMPLE 12 2-(2-Chlorophenyl-aminocyclopent-1-ene-carbonitrile(Intermediate leading to (22))

2-Chloroaniline (Aldrich Chemicals) (2.6 g, 20.4 mmol),2-oxo-cyclopentane-carbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 nml) were heated under refluxfor 16 hours. This mixture was filtered and the solvent evaporated.Kugelrohr distillation (150° C., 0.5 mmHg) of the residue gave a paleyellow oil which slowly crystallised over time.

m.p. 69-72° C. (Found: C, 65.7; H, 5.0; N, 12.6; Cl, 16.35. C₁₂ H₁₁ ClN₂requires C, 65.9; H, 5.1; N, 12.8; Cl, 16.2%. δH (250 MHz: CDCl₃) 2.00(2H, quin, J=7.4, CH-4), 2.62 (2H, t, J=7.2, CH₂ -3) , 2.70 (2H, t,J=7.5, CH₂ -5), 6.69 (1H, br s, NH), 7.03 (1H, ddd, J=8.4, 7.5 and 1.7,Ar--H-4-) 7.21 (1H, ddd, J=8.1, 7.1 and 1.8, Ar--H-5-) 7.22 (1H, dd,J=7.2 and 1.0, Ar--H-6-), 7.39 (1H, dd, J=8.0 and 1.3, Ar--H-3⁻).

EXAMPLE 13 9-Amino-5-chloro-2,3-dihydro-1H-cyclopenta[b] quinoline (22)

Substituted aniline (Example 12) (2.2 g, 10.0 mmol) and titaniumtetrachloride (1.2 ml, 11.0 mmol) under a dry nitrogen atmosphere wereheated together at 140° C. for 1 hour. After cooling, 10M-sodiumhydroxide (20 ml) was added and the mixture was heated under reflux for1 hour. Any organic components were extracted into dichloromethane dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(225° C., 0.5 mmHg) gave the product as pale yellow crystals.

m.p. 249-250° C. (dec). (Found: C, 66.0; H, 5.3; N, 12.8; Cl, 156.4, C₁₂H₁₁ ClN₂ requires C, 65.9; H, 5.1; N, 12.8; Cl, 16.2%). δH[250 MHz;(CD₃)₂ SO] 2.08 (2H, quin, J=7.5, CH₂ -2), 2.82 (2H, t, J=7.3, CH₂ -1),2.94 (2H, t, J=7.7, CH₂ -3), 6.62 (2H, s, NH₂), 7.25 (1H, dd, J=8.4 and7.6, Ar--H-7), 7.67 (1H, dd, J=7.4 and 1.2, Ar--H-8), 8.12 (1H, dd,J=8.4 and 1.2, Ar--H-6).

EXAMPLE 14 2-(4-Chlorophenyl) amino-cyclopentene-1-carbonitrile(Intermediate of (19))

4-Chloro-aniline (Aldrich Chemicals) (2.6 g, 20 mmol), cyanoketone(Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) andT.H.F. (30 ml) were heated under reflux for 19 hours. After beingallowed to cool, the mixture was filtered and the solvent evaporated.Kugelrohr distillation (160° C., 0.3 mm Hg) gave the product as whitecrystals.

m.P. 130-132° C. (Found: C, 65.9; H, 5.0; N, 12.7; Cl, 16.5; C₁₂ H₁₁ClN₂ requires C, 65.9; H. 5.1; N, 12.8; Cl. 16.2%). δH (250 MHZ; CDCl₃)1.97 (2H, quin, J=7.4, CH₂ -4), 2.59 (2H, tt, J=8.0, 1.3 CH₂ -3), 2.66(2H, t, J=7.6, CH₂ -5), 6.80 (1H, br s, NH), 6.96 (2H, dt, J=9.4, 2.6,Ar--H-2',6'), 7.26 (2H, dt, J=9.4, 2.6. Ar--H-3', 5'). m/z 218.0597 (M⁺,100%), 220.0572 (M⁺ +2, 36%).

EXAMPLE 15 9-Amino-7-chloro-2,3-dihydro-1H-cyclopenta-[b] quinoline (19)

Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added tothe above enamine (Example 14) (2.2 g, 10 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (20 ml) was added and the mixture heated under reflux for 1hour. After being allowed to cool, this mixture was filtered and thesolids washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extracts were combined, dried(Na₂ SO₄), filtered and the solvent evaporated, Kugelrohr distillation(200° C., 2 mm Hg) gave the product as a pale yellow powder.

m.p. 228-230° C. (dec). (Found: C, 65.8; H, 5.0; N, 12.7; Cl, 6.2. Calc,for C₁₂ H₁₁ ClN₂ C, 65.9; H, 5.1; N, 12.8; Cl, 16.2%). δH(250 MHz;(CD₃)₂ SO], 2.02 (2H, quin, J=7.4, CH₂ -2), 2.80 (2H, t, J=7.3, CH₂ -1),2.89 (2H, t, J=7.7, CH₂ -3), 6.54 (2H, s, NH₂), 7.48 (1H, dd, J=9.0,2.3, Ar--H-6), 7.67 (1H, d, J=8.9, Ar--H-5), 8.26 (1H, d, J=2.2,Ar--H-8).

EXAMPLE 16 2-(2'Fluorophenyl) amino-cyclopentene-1-carbonitrile(Intermediate leading to (13))

2-Fluoro-aniline (Aldrich Chemicals) (2.3 g, 21 mmol), cyanoketone(Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) andT.H.F. (30 ml) were heated under reflux for 24 hours. After beingallowed to cool, the mixture was filtered and the solvent evaporated.Kugelrohr distillation (125° C. 0.05 mm Hg) have the product as anoff-white power.

m.p. 91-92° C. (Found: C, 71.1; H, 5.5; N, 13.7. C₁₂ H₁₁ FN₂ requires C,71.3; H, 5.5; N, 13.85%) δH (250 MHz; CDCl₃) 1.99 (2H, quin, J=7.3, CH₂-4), 2.68 (2H, t, J=7.4, CH₂ -3), 2.61 (2H, t, J=7.8, CH₂ -5), 6.44 (1H,Br s, NH, 7.07-7.19 (4H, m, Ar--H). δF (377 MHz; CDCl₃)-127.5 (s,Ar--F-2').

EXAMPLE 17 9-Amino-5-fluoro-2,3-dihydro-1H-cyclopenta-[1,2-b] quinoline(13)

Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added tothe above enamine (Example 8) (2.0 g, 10 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (20 ml) was added and the mixture heated under reflux for 1hour. After being allowed to cool, this mixture was filtered and thesolids washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extracts were combined, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(175° C., 0.04 mm Hg) gave the product as an off-white powder.

m.p. 257-260° C. (dec). (Found: C, 71.3; H, 5.3; N, 13.7, C₁₂ H₁₁ FN₂requires C, 71.3; H, 5.5; N, 13.85%). δH [400 MHz; (CD₃)₂ SO] 2.06 (2H,quin, J=7.5, CH₂ -2, 2.83 (2H, t, J=7.3, CH₂ -1), 2.92 (2H, t, J=7.7,CH₂ -3), 6.54 (2H, s, NH₂), 7.24 (1H, td, J=7.9, 5.4, Ar--H-7), 7.30(1H, ddd, J=11.2, 7.6, 1.2, Ar--H-8).

EXAMPLE 18 2-(3'-Fluorophenyl) amino-cyclopentene-1-carbonitrile(Intermediate leading to 15))

3-Fluoro-aniline (Aldrich Chemicals) (4.6 g, 41 mmol), cyano-ketone(Example 11) (4.4 g, 40 mmol), calcium chloride (5.0 g, 45 mmol) andT.H.F. (60 ml) were heated under reflux for 17 hours. After beingallowed to cool, the mixture was filtered and the solvent evaporated.Kugelrohr distillation (125° C., 0.02 mm Hg) gave the product as a paleyellow powder.

m.p. 98-100° C. (Found: C, 71.25; H. 5.25; N, 14.0. C₁₂ H₁₁ FN₂ requiresC, 71.3; H, 5.5; N, 13.85%). δH (250 MHz; CDCl₃) 1.99 (2H, quin, J=7.4,CH₂ -4), 2.59 (2H, tt, J=7.2, 1.4, CH₂ -5), 2.73 (2H, t, J=7.5, CH₂ -3),6.70-6.80 (3H, m, Ar--H-4, 5 and 6), 6.96 (1H, br s, NH), 7.20-7.30 (1H,m, Ar--H-2). δF (377 MHz; CDCl₃) 111.9 (m, Ar--F-3).

EXAMPLE 19 9-Amino-8-fluoro-2,3-dihydro-1H-cyclopenta-[b] quinoline (14)and 9-amino-6-fluoro-2,3-dihydro-1H-cyclopenta [b] quinoline (15)

Under nitrogen, titanium tetrachloride (2.4 ml, 22 mmol) was added tothe above enamine (Example 18) (4.0 g, 20 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (40 ml) was added and the mixture heated under reflux for 1hour. After being allowed to cool, this mixture was filtered and thesolids washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extracts were combined, dried(Na₂ SO₄), were filtered and the solvent evaporated. Kugelrohrdistillation (150-175° C., 0.05 mm Hg) followed by chromatography onsilica with chloroform-ethanol-10M ammonia solution (100:8:1) as theeluant gave two products. Kugelrohr distillation of the first fraction(170° C., 0.8 mm Hg) gave an off-white powder (14). A similardistillation of the second fraction (175° C., 0.7 mm Hg) gave a whitepowder (14).

m.p. 172-173° C. (14). (Found: C, 71.1; H, 5.7; N, 13.9. calc. for C₁₂H₁₁ FN₂ C, 71.3; H, 5.5; N, 13.85%). δH[400 MHz; (CD₃)₂ SO] 2.00 (2H,quin, J=7.5, CH₂ -3), 2.75 (2H, t, J=7.2, CH₂ -1), 2.84 (2H, t, J=7.78,CH₂ -3), 6.19 (2H, s, NH₂), 6.98 (1H, ddd, J=13.8, 7.3, 1.4, Ar--H-7),7.37 (1H, td, J=8.0, 6.0, Ar--H-6), 7.45 (1H, dd, 8.6, 1.4, Ar--H-5).δF[377 MHz; (CD₃)₂ SO] 144.4(m, Ar--F-8). m.p. 235-236° C. (15). (Found:C, 71.4; H, 5.5; N, 13.8. C₁₂ H₁₁ FN₂ requires C, 71.3; C, 5.5; N,13.85%). δH[400 MHz; (CD₃)₂ SO] 2.05 (2H, quin, J=7.5, CH₂ -2), 2.80(2H, t, J=7.3, CH₂ -1), 2.89 (2H, t, J=7.7, CH₂ -3), 6.52 (2H, s, NH₂),7.19 (1H, td, J=8.7, 2.7, Ar--H-7), 7.34 (1H, dd, J=11.1, 2.7, Ar--H-5),8.20 (1H, dd, J=9.2, 6.4, Ar--H-8). δF[377 MHz; (CD₃)₂ SO] 113.8 (m,Ar--F-6).

EXAMPLE 20 2-(4'-Fluorophenyl) amino-cyclopentene-1-carbonitrile(Intermediate leading to (11))

4-Fluoro-aniline (Aldrich Chemicals) (2.3 g, 21 mmol), cyano-ketone(Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) andT.H.F. (30 ml) were heated under reflux for 21 hours. After beingallowed to cool, the mixture was filtered and the solvent evaporated.Kugelrohr distillation (160° C., 0.4 mm Hg) gave the product as anoff-white powder.

m.p. 100-102° C. (Found: C, 71.3; H, 5.5; N, 13.8, C₁₂ H₁₁ FN₂ requiresC, 71.3; H, 5.5; N, 13.85%). δH (250 MHz; CDCl₃) 1.95 (2H, quin, J=7.4,CH₂ -4), 2.58 (4H, t, J=7.4, CH₂ -3 and 5), 6.66 (1H, br s, NH), 7.00(2H, s, Ar--H-2' and 6'), 7.02 (2H, s, Ar--H-3' and 5'). δF (377 MHz;CDCl₃) 118.4(s, Ar--F-4').

EXAMPLE 21 9-Amino-7-fluoro-2,3-dihydro-1H-cyclopenta-[b] quinoline (11)

Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added tothe above enamine (Example 20) (2.0 g, 10 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (20 ml) was added and the mixture heated under reflux for 1hour. After being allowed to cool, this mixture was filtered and thesolids washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extracts were combined, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(175° C., 0.05 mmHg) gave the product as an off-white powder.

m.p. 230-232° C. (dec). (Found: C, 71.0; H, 5.5; N, 13.9 C₁₂ H₁₁ FN₂requires C, 71.3; H, 5.5; N, 13.85%). δH[250 MHz; (CD₃)₂ SO] 2.05 (2H,quin, J=7.5, CH₂ -2), 2.80 (2H, t, J=7.3, CH₂ -1), 2.88 (2H, t, J=7.7,CH₂ -3), 6.41 (2H, s, NH₂), 7.38 (1H, td, J=8.7, 2.8, Ar--H-6), 7.71,(1H, dd, J=9.2, 5.8, Ar--H-5), 7.93 (1H, dd, J=11.1, 2.8, Ar--H-8).δF[377 MHz: (CD₃)₂ SO]-118.1 (s, Ar--F-7).

EXAMPLE 22 2-(4'Bromophenyl) amino-cyclopentene-1-carbonitrile(Intermediate leading to 25))

4-Bromo-aniline (Aldrich Chemicals) (3.5 g, 20 mmol), cyano-ketone(Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) andT.H.F. (30 ml) were heated under reflux for 7 hours. After being allowedto cool, the mixture was filtered and the solvent evaporated. Kugelrohrdistillation (150° C., 0.07 mmHg) gave the product as a brown-greypowder.

m.p. 136-138° C. (Found: C, 55.0; H, 4.3; N, 10.8; Br, 30.6. calc. forC₁₂ H₁₁ BrN₂ C, 54.8; H, 4.2; N, 10.65; Br, 30.4%. δH (250 MHz, CDCl₃)1.98 (2H, quin, J=7.4, CH₂ -4), 2.59 (2H, tt, J=7.2, 1.5. CH₂ -4), 2.67(2H, t, J=7.5, CH₂ -3), 6.68 (1H, br s, NH), 6.90 (2H, d, J=8.8,Ar--H-2' and 6'), 7.41 (2H, d, J=8.8, Ar--H-3' and 5').

EXAMPLE 23 9-Amino-7-bromo-2,3-dihydro-1H-cyclopenta-[1,2-b] quinoline(25)

Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added tothe above enamine (Example 22) (2.6 g, 20 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (20 ml) was added and the mixture heated under reflux for 1hour. After being allowed to cool, this mixture was filtered and thesolids washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extracts were combined, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(180° C., 0.04 mmHg) gave the product as a pale yellow powder.

m.p. 236-238° C. (Found: C, 54.75; H. 4.1; N, 10.7; Br, 30.4/ C₁₂ H₁₁BrN₂ requires C, 24.8; H, 4.2; N, 10.65; Br, 30.4%. δH[250 MHz; (CD₃)₂SO] 2.04 (2H, quin, J=7.5, CH₂ -2), 2.80 (2H, t, J=7.3, CH₂ -1), 2.88(2H, t, J=7.7, CH₂ -3), 6.55 (2H, s, NH₂), 7.60 (2H, s, Ar--H-5 and 6),8.40 (1H, m, Ar--H-8).

EXAMPLE 24 2-(3'-Chlorophenyl)aminocyclopent-1-ene-carbonitrile.(Intermediate leading to (16) and (17))

3-Chloro-aniline (Aldrich Chemicals) (5.1 g, 40.0 mmol), cyano-ketone(Example 11) (4.4 g, 40.4 mmol) and calcium chloride (5.0 g, 45.0 mmol)in T.H.F. (60 ml) were heated under reflux for 17 hours. After cooling,the mixture was filtered and the solvent evaporated. Kugelrohrdistillation (150° C., 0.2 mmHg) gave the product as light yellowpowder.

m.p. 111-112° C. (Found: C, 65.9; H, 5.1; N, 12.6; Cl, 16.5. C₁₂ H₁₁ClN₂ requires C, 65.9; H, 5.1; N, 12.8; Cl, 16.2%). δH (250 MHz; CDCl₃)1.99 (2H, quin, J=7.4, CH₂ -4), 2.60 (2H, tt, J=7.2, 1.5 CH-5), 2.72(2H, t, J=7.5, CH₂ -3), 6.77 (1H, br s, NH, 6.90) (1H, ddd, J=8.1, 2.1,1.3, Ar--H-4'), 7.02 (1H, dd, J=2.0, 2.0, Ar--H-2'), (1H, ddd, J=9.8,1.9, 1.0, Ar--H-6'), 7.23 (1H, dd, J=8.0, 8.0, Ar--H-5').

EXAMPLE 25 9-Amino-8-chloro-2,3-dihydro-1H-cyclopenta[b]quinoline and9-amino-6-chloro-2,3-dihydro-1H-cyclopenta[b] quinoline (16) and (17)

Under nitrogen, titanium tetrachloride (2.4 ml, 22 mmol) was added tothe above enamine (Example 24) (4.4 g, 20 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (40 ml) was added and the mixture heated reflux for 1 hour.After being allowed to cool, this mixture was filtered and the solidswashed with dichloromethane. Any organics in the filtrate were alsoextracted into dichloromethane. All extractions were combined, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(175-200° C., 0.02 mmhg) followed by chromatography on silica withchloroform-ethanol-10M ammonia solution (200:8:1) as the eluent gave twoproducts. Kugelrohr distillation of the first fraction (160° C., 0.08mmHg) gave a white powder (16). A similar distillation of the secondfraction (200° C., 0.03 mmHg) gave an off-white powder (17).

i) m.p. 185° (16)

(Found: C,65.95; H. 5.35; N, 12.8; Cl, 16.2. calc. for C₁₂ H₁₁ ClN₂ ; C,65.9; H, 5.1; N, 12.8; Cl, 16.2%). δH [250 MHz; (CD₃)₂ SO] 2.07 (2H,quin, J=7.6, CH₂ -2), 2.79 (2H, t, J=7.3, CH₂ -1), 2.91 (2H, t, J=7.7,CH₂ -3), 6.53 (2H, br s, NH₂), 7.34 (1H, dd, J=7.5, 1.5. Ar--H-7), 7.42(1H, t, J=7.8, Ar--H-6), 7.65 (1H, dd, J=8.2, 1.5, ArH-5)

ii) m.p. 271-272° C. (dec) (17)

(Found: C, 65.5; H, 4.9; N, 12.7; Cl, 17.4. C₁₂ H₁₁ ClN, requires C,65.9; H, 5.1; N, 12.8; Cl, 16.2%). δH[250 MHz; (CD₃)₂ SO] 2.06 (2H,quin, J=7.5, CH₂ -2), 2.80 (2H, t, J=7.3, CH₂ -1), 2.91 (2H, t, J=7.7,CH₂ -3), 6.77 (2H, br s, NH₂), 7.34 (1H, dd, J=8.9, 2.2, Ar--H-7), 7.68(1H, d, J=2.2, Ar--H-5), 8.18 (1H, d, d=9.0, Ar--H-8).

EXAMPLE 26 2-(2',4'-Difluorophenyl)aminocyclopent-1-ene-1-carbonitrile(Intermediate leading to 32)

2,4-Difluoro-aniline (2.6 g, 20.0 mmol) (Aldrich Chemicals) cyano-ketone(Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) andT.H.F. (30 ml) were heated under reflux for 19 hours. After cooling, themixture was filtered and the solvent evaporated. Kugelrohr distillation(125° C., 0.25 mmHg) gave the product as pale yellow crystals.

m.p. 116-119° C. (Found: C, 65.3; H, 4.9; N, 12.4. C₁₂ H₁₀ F₁ N₂requires C, 65.54; H, 4.6; N, 12.7%. δH (400 MHz; CDCl₃) 1.96 (2H, quin,J=7.4, CH₂ -4), 2.56 (2H, tt, J=7.8, 2.4, CH₂ -5), 2.60 (2H, tt, J=7.2,1.5, CH₂ -3), 6.26 (1H, Br s, NH), 6.85 (1H, td, J=8.3, 2.7, Ar--H-3'),6.88 (1H, dddd, J=9.1, 7.9, 2.8, 1.5, Ar--H-5') 7.15 (1H, td, J=9.0,5.7, ArH-6'). δF (377 MHz; CDCl₃) 113.49 (1F, tt, J=8.1, 5.7, Ar--F-4'),121.09 (1F, td, J=9.5, 5.7, Ar--F-2').

EXAMPLE 27 9-Amino-5,7-difluoro-2.3dihydro-1H-cyclopenta[1,2b]quinoline(32)

Under nitrogen, titanium tetrachloride (1.2 ml, 11 mmol) was added tothe above enamine (Example 26) (2.2 g, 10 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxide(20 ml) was added and the mixture heated under reflux for 1 hour. Afterbeing allowed to cool, this mixture was filtered and the solid washedwith dichloromethane. Any organics in the filtrate were also extractedinto dichloromethane. All extracts were combined, dried (Na₂ SO₄),filtered and the solvent evaporated. Kugelrohr distillation (175° C.,0.08 mmHg) gave the product as a yellow powder.

m.p. 250° C. (dec) (Found: C, 65.7; H, 4.8; N, 12.7. C₁₂ H₁₀ F₂ N₂requires C, 65.45; H, 4.6; N, 12.7%). δH[400 MHz; (CD₃)₂ SO] 2.07 (2H,quin, J=7.5, CH₂ -2), 2.82 (2H, t, J=7.3, CH₂ -1), 2.91 (2H, t, J=7.7,CH₂ -3), 6.54 (2H, s, NH₂), 7.40 (1H, ddd, J=11.3, 8.8, 2.6, Ar--H-6),7.81 (1H, ddd, J=10.9, 2.5, 1.6. Ar--H-8). δF[377 MHz; (CD₃)₂ SO]-115.96(1F, ddd, J=10.7, 9.0, 5.7, Ar--F-7) 120.10 (1F, ddd, J=11.1, 5.8, 1.4,Ar--F-5).

EXAMPLE 28 2-(2'5'-Difluorophenyl) aminocyclopent-1-ene-1-carbonitrile(Intermediate leading to 31)

2,5-Difluoro-aniline (2.6 g, 20.0 mmol) (Aldrich Chemicals) cyano-ketone(Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) andT.H.F. (30 ml) were heated under reflux for 22 hours. After cooling, themixture was filtered and the solvent evaporated. Kugelrohr distillation(160° C., 0.9 mmHg) gave the produce as white crystals.

m.p. 102-103° C. (Found: C, 65.7; H, 4.75; N. 12.75. C₁₂ H₁₀ F₂ N₂requires C, 65.45; H, 4.6; N, 12.7%) δH (400 MHz; CDCl₃) 2.04 (2H, quin,J=7.4, CH₂ -4), 2.63 (2H, tt, J=7.3, 1.6, CH₂ -5), 2.75 (2H, t, J=7.6,CH₂ -2), 6.51 (1H, Br s, NH), 6.72 (1H, ddt, J=9.0, 7.5, 3.3, Ar--H-4'),6.86 (1H, ddd, J=9.5, 6.6, 3.0, Ar--H-6'), 7.06 (1H, ddd, J=10.0, 9.1,5.0, Ar--H-3'). δF (377 MHz; CDCl₃) 116.94 (1F, dddd, J=1.0, 7.1, 3.6,0.8, Ar--F-5'), 134.79 (IF, dddd, J=10.2, 6.4, 3.8, 2.7, Ar--F-2').

EXAMPLE 29 9-Amino-5,8-difluoro-2,3-dihydro-1H-cyclopenta[1.2b]quinoline (31)

Under nitrogen, titanium tetrachloride (0.9 ml, 8.2 mmol) was added tothe above enamine (Example 28) (1.65 G, 7.5 mmol) and the stirredmixture was heated at 140° C. for 1 hour. After cooling, 10M-sodiumhydroxide solution (20 ml) was added and the mixture heated under refluxfor 1 hour. After being allowed to cool, this mixture was filtered andthe solids washed with dichloromethane. Any organics in the filtratewere also extracted into dichloromethane. All extracts were combined,dried (Na₂ SO₄), filtered and the solvent evaporated. Kugelrohrdistillation (170° C., 0.06 mmHg) gave the product as a yellow powder.

m.p. 168-171° C. (Found: C, 65.3; H, 4.6; N, 12.8. C₁₂ H₁₀ F₂ N₂requires C, 65.45; H, 4.6; N, 12.7%). δH[400 MHz; (CD₃)₂ SO] 2.07 (2H,quin, J=7.6, CH₂ -2), 2.82 (2H, t, J=7.4, CH₂ -1), 2.93 (2H, t, J=7.7,CH₂ -3), 6.39 (2H, s, NH₂), 7.01 (1H, ddd, J=12.8, 8.6, 4.1. Ar--H-7),7.28 (1H , ddd, J-10.6, 8.7, 4.6, Ar--H-6). δH[377 MHz; (CD₃)₂SO]-128.18 (1F, dd, J=10..5, 3.9. Ar--F-8), 128.23 (1F, dd, J=10.6, 4.0,Ar-F-5).

EXAMPLE 30 2-(3', 4'-Difluorophenyl)aminocyclopent-1-ene-1-carbonitrile. (Intermediate leading to (10) and(8))

3,4'Difluoro-aniline (Avocado) (5.0 g, 38.8 mmol), cyano-ketone (Example11) (4.3 g, 39.4 mmol), calcium chloride (4.5 g, 40.5 mmol) and T.H.F.(60 ml) were heated under reflux for 18 hours. After cooling, themixture was filtered and the solvent evaporated. Kugelrohr distillation(150° C., 0.1 mmHg) gave the product as a pale pink powder.

m.p. 126-128° C. (Found: C, 65.3; H, 4.7; N, 13.0. C₁₂ H₁₁ F₂ N₂requires C, 65.45; H, 4.6; N, 12.7%). δH (400 MHz: CDCl₃) 1.99 (2H,quin, J=7.4, CH₂ -4), 2.60 (2H, tt, J=7.2, 1.5, CH₂ -5), 2.64 (2H, tt,J=7.5, 1.4, CH₂ -3), 6.57 (1H , br s, NH), 6.76 (1H , tdt, J-8.4, 4.0,1.8, Ar--H-6'), 6.88 (1H , dd, J=11.3, 6.8, 2.7, Ar--H-2'), 7.11 (1H ,dt, J=9.9, 8.8, Ar--H-5'). δF (377 MHz; CDCl₃)-135 (1F, dddd, J=21.6,11.3, 8.7, 1.7, Ar--F-3').-143.21 (1F, dddd, J=21.5, 10.2, 6.8, 3.7,Ar--F-4').

EXAMPLE 31 2-Aminocyclohex-1-ene-1-carbonitrile (Intermediate leading to(18))

1,5-Dicyanopentane (Aldrich Chemicals) (25.0 g, 205 mmol), sodiumhydride (60% oil dispersion; 8.2 g, 205 mmol) and T.H.F. (150 ml) wereheated under reflux for 17 hours. After cooling, water (150 ml) wasadded and the upper organic layer removed, dried (Na₂ SO₄) filtered andthe solvent evaporated. Recrystallisation from hot toluene (80° C.) gavethe product as beige crystals.

m.p. 90-92° C. (Found: c, 68.8; H, 8.5; N, 23.0. Calc. for C₇ H₁₀ N₂ :C, 68.8; H, 8.25; N, 22.9%). δH[250 MHz; (CD₃)₂ SO] 1.52 (4H, m, CH₂ -4and 5), 2.05 (2H, t, J=4.4, CH₂ -3, 2.07 (2H, t, 4.4. CH₂ -6), 5.80 (2H,br s, NH₂).

EXAMPLE 32 2-Oxocyclohexane-1-carbonitrile (Intermediate leading to(18))

The above cyano-enamine (Example 31) (16.0 g, 131 mmol) and1M-hydrochloric acid (150 ml) were stirred at room temperature for 17hours. The suspension was saturated with ammonium chloride and theorganic components were extracted into diethyl ether, dried (Na₂ SO₄),filtered and the ether was evaporated. Kugelrohr distillation (100° C.,0.2 mmHg) gave the product as a colourless liquid.

(Found: C, 68.6; H, 7.6; N, 11.5. Calc. for C₇ H₉ NO: C, 68.3; H, 7.4;N, 11.4%). δ_(H) (250 MHz: CDCl₃ 1.58-2.54 (8H, m, CH₂), 3.54 (1H , dd,J=11.6, 5.5, CHCN).

EXAMPLE 33 2-(4'Fluorophenyl) aminocyclohex-1-ene-1-carbonitrile(Intermediate leading to (18))

4-Fluoro-aniline (1.11 g, 10.0 mmol), cyano-ketone (Example 32) (1.25 g,10.2 mmol), calcium chloride (1.5 g, 13.5 mmol) and T.H.F. (20 ml) wereheated under reflux for 17 hours. After cooling, the mixture wasfiltered and the solvent evaporated. Kugelrohr distillation (135° C.,0.08 mmHg) gave the product as a pale yellow powder.

m.p. 79-82° C. (Found: C, 72.0; H, 6.3; N, 13.1. C₁₃ H₁₃ FN₂ requires C,72.2; H, 6.1; N, 12.95%). δ_(H) (400 MHz; CDCl₃) 1.64 (4H, m, CH₂ -4 and5), 2.15 (2H, m, CH₂ -6), 2.29 (2H, m, CH₂ -3), 6.37 (1H , br s, NH),7.00 (2H, s, Ar--H-2' and 6'), 7.02 (2H, s, Ar--H-3' and 5'). δ_(F) (377MHz; CDCl₃) 117.64 (1F quin, J=6.5, 0.8, Ar--F-4').

EXAMPLE 34 9-Amino-7-fluoro-1, 2, 3, 4-tetrahydro-acridine (18)

Under nitrogen, titanium tetrachloride (0.9 ml, 8.2 mmol) was added tothe above enamine (Example 33) (1.5 g, 7.5 mmol) and the stirred mixturewas heated at 140° C. for 1 hour. After cooling, 10M-sodium hydroxidesolution (20 ml) was added and the mixture heated under reflux for 1hour. After being allowed to cool, this mixture was filtered and thesolids washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extracts were combined, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(175° C., 0.05 mmHg) gave the product as a pale yellow powder.

m.p. 229-230° C. (Found: C, 72.4; H, 6.15; N, 13.2. C₁₃ H₁₃ N₂ Frequires C, 72.2; H, 6.1; N, 12.95%). δ_(H) (400 MHz; (CD₃)₂ SO] 1.80(4H, m, CH₂ -2 and 3), 2.55 (2H, t, J=6.0, CH₂ -1), 2.81 (2H, t, J=5.9,CH₂ -4), 6.28 (2H, s, NH₂), 7.37 (1H , td, J=8.8, 2.8, Ar--H-6), 7.74(1H, dd, J=9.2, 5.8, Ar--H-5), 7.95 (1H, dd, J=11.2, 2.8, Ar--H-8). δF[377 MHz, (CH₃)₂ SO] 117.87 (ddd. J=11.1, 8,3, 5.8, Ar--F-7).

EXAMPLE 35 9-Amino-7,8-difluoro-2,3-dihydro-1-H-cyclopenta-[1,2-b]quinoline and 9-amino-6,7-difluoro-2,3-dihydro-1H -cyclopenta [1,2-b]quinoline (10) and (8)

Under nitrogen, titanium tetrachloride (2.4 ml, 22 mmol) was added to2-(3',4'-difluorophenyl) aminocyclopent-1-ene-1-carbonitrile (Example30) (4.4 g, 20 mmol) and the stirred mixture was heated at 140° C. for 1hour. After cooling, 10M-sodium hydroxide (40 ml) was added and themixture heated under reflux for 1 hour. After being allowed to cool,this mixture was filtered and the solid washed with dichloromethane. Anyorganics in the filtrate were also extracted into dichloromethane. Allextracts were combined, dried (Na₂ SO₄), filtered and the solventevaporated. Kugelrohr distillation (175-225° C., 0.15 mmHg) followed bychromatography on silica with chloroform-ethanol-10M ammonia solution(200:8:1) as the eluant gave two products. Kugelrohr distillation of thefirst fraction (140° C., 0.07 mmHg) gave a pale yellow powder. A similardistillation of the second fraction (200° C., 0.1 mmHg) gave anoff-white powder.

i) m.p. 177-178° C. (10)

(Found: C, 65.3; H, 4.3; N, 12.65. C₁₂ H₁₀ F₂ N₂ requires C, 65.45; H,4.6; N, 12.7%) δ_(H) [250 MHz; (CD₃)₂ SO] 2.05 (2H, quin, J=7.5, CH₂-2), 2.81 (2H, t, J=7.4, CH₂ -1), 2.89 (2H, t, J=7.7, CH₂ -3), 6.31 (2H,s, NH₂), 7.49-7.64 (2H, m, Ar--H-5 and 6).

ii) m.p. 263-265° C. (dec). (8)

(Found: C, 65.3; H, 4.5; N, 12.7. C₁₂ H₁₀ F₂ N₂ requires C, 65.45; H,4.6; N, 12.7%) δ_(H) [250 MHz; (CD₃)₂ SO] 2.04 (2H, quin, J=7.5, CH₂-2), 2.79 (2H, t, J=7.3, CH₂ -1), 2.87 (2H, t, J=7.7, CH₂ -3), 6.54 (2H,s, NH₂), 7.59 (1H , dd, J=12.5, 8.2, Ar--H-8), 8.18 (1H , dd, J=12.9,8.9, Ar--H-5).

EXAMPLE 36

1-(4'Fluorophenyl) amino-2-cyano-3,4-dihydro-naphthalene (Intermediateleading to (27))

4-Fluoro-aniline (Aldrich Chemicals) (1.11 g, 10 mmol) and 2-cyano-3,4-dihydro-1 (2H) -naphthalenone (synthesised according to the method ofJohnson. W. S. and Shelberg W. E. J. Amer. Chem. Soc., (1945), 67p.1745.) (91.71 g 10 mmol) were heated together at 150° C. for 1 hour.After cooling, chromatography on silica with chloroform as the eluentfollowed by Kugelrohr distillation (175° C., 0.2 mmHg) gave the productas pale brown crystals.

m.p. 151-153° C. (Found: C, 77.0; H, 5.0; N, 10.8. C₁₇ H₁₃ FN₂ requiresC, 77.3; H, 5.0; N, 10.6%). δH (250 MHz; CDCl₃) 2.51 (2H, t, J=7.4, CH₂-3), 2.90 (2H, t, J=7.4, CH₂ -4), 6.33 (1H , br s, NH), 6.75 (2H, ABX,J=8.9, 4.6, Ar--H-2' and 6'), 6.91 (2H, ABX, J=8.6, 8.6, Ar--H-3e and5'), 7.08 (1H, dd, J=7.0, 5.9, 2.3 Ar--H-7), 7.19 (1H , d, J=7.7,Ar--H-5), 7.26 (1H, d, J=6.7, Ar--H-8), 7.27 (1H , td, J=6.9, 1.3,Ar--H-5), 7.26 (1H , d, J=6.7, Ar--H-8), 7.27 (1H , td, J=6.9, 1.3,Ar--H-6).

EXAMPLE 37 7-Amino-9-fluoro-5,6-dihydrobenz[c] acridine (27)

Under nitrogen, titanium tetrachloride (0.3 ml, 2.7 mmol) was added tothe above enamine (Example 36) (0.65 g, 2.5 mmol) and the stirredmixture was heated at 140° C. for 1 hour. After cooling, 10M-sodiumhydroxide (20 ml) was added and the mixture heated under reflux for 1hour After being allowed to cool, this mixture was filtered and thesolid washed with dichloromethane. Any organics in the filtrate werealso extracted into dichloromethane. All extractions were combined,dried (Na₂ SO₄), filtered and the solvent evaporated. Kugelrohrdistillation (210° C., 0.07 mmHg) gave the product as a pale yellowpowder.

m.p. 158-159° C. (Found: C, 77.0; H, 5.0; N, 10.8. C₁₇ H₁₃ FN₂ requiresC, 77.3; H, 5.0; N, 10.6%). δH[250 MHz; (CD₃)₂ SO] 2.86 (4H, s, CH₂ -3and 4), 6.57 (2H, s, NH₂), 7.25-7.37 (3H, m, Ar--H-5, 6 and 7), 7.46 (1H, td, J=8.7, 2.7, Ar--H-11), 7.85 (1H , dd, J=9.2, 3.4, Ar--H-10), 8.03(1H , dd, J=l1.1, 2.8, Ar--H-13), 8.35 (1H , dd, J=7.3, 5.4, Ar--H-8).

EXAMPLE 38 2-(3', 5'-Difluorophenylamino)-cyclopent-1-ene-1-carbonitrile(Intermediate leading to (9))

3,5-Difluoro-aniline (Aldrich Chemicals) (2.6 g, 20.0 mmol),2-oxocyclopentane carbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. were heated under reflux for 24hours. After cooling the mixture was filtered and the solventevaporated. Kugelrohr distillation (140° C., 0.3 mmHg) gave the productas pale yellow crystals.

m.p. 113-115° C. (Found: C, 65.2; H, 4.3; N, 12.5. C₁₂ H₁₀ F₂ N₂requires C, 65.45; H, 4.6; N, 12.7%). δH(250 MHz; CDCl₃) 2.02 (2H, quin,J=7.4, CH₂ -4), 2.60 (2H, tt, J=7.6, 1.5, CH₂ -5), 2.77 (2H, t, J=7.5,CH₂ -3), 6.50 (1H, tt, J=9.0, 2.2, Ar--H-4'), 6.53 (2H, dd, J=10.3, 1.4,Ar--H-2' and 6'), 7.01 (1H , br s, NH). δF (377 MHz; CDCl₃)-108.997 (t,J=8.8, Ar--F-3' and 5').

EXAMPLE 39 9-Amino-6,8-difluoro-2.3-dihydro-1H -cyclopenta[1,2-b]quinoline (9)

Under nitrogen, titanium tetrachloride (1.2 ml; 2.1 g; 11.0 mmol) wasadded to the above enamine (Example 38) (2.2 g, 10.0 mmol) and thestirred mixture was heated at 140° C. for 1 hour. After cooling, sodiumhydroxide (10M, 20 ml) was added and the mixture heated under reflux for1 hour. After being allowed to cool, this was filtered and the solidswere washed with dichloromethane. Any organics in the filtrate were alsoextracted into dichloromethane, the extracts were combined, dried (Na₂SO₄), filtered and the solvent evaporated. Kugelrohr distillation (180°C., 0.02 mmHg) gave the product as a very pale yellow powder.

(Found: C, 65.25; H, 4.25; N, 12.65. C₁₂ H₁₀ F₂ N₂ requires C, 65.45; H,4.6; N, 12.7%. νmax 3515, 3311 (NH₂). δH[250 MHz; (CD₃)₂ SO] 2.04 (2H,quin, J=7.5, CH₂ -2), 2.78 (2H, t, J=7.3, CH₂ -1), 2.88 (2H, t, J=7.7,CH₂ -3), 6.38 (2H, br s, NH₂), 7.14 (1H, ddd, J=13.6, 9.2, 2.7;Ar--H-7), 7.22 (1H, ddd, J=10.7, 2.6, 1.3, Ar--H-5). δF [377 MHz; (CD₃)₂SO] -109.73 (1F, dd, J=13.3, 8.11, Ar--F-8) 111.65 (1F, dt, J=10.6, 8.6,Ar--F-6).

EXAMPLE 40 2-(2'-Methylphenyl)-aminocyclopent-1-enecarbonitrile

2-methylaniline (Avocado) (2.2 g, 20.6 mmol),2-oxocyclopentanecarbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under refluxfor 16 hours. After cooling, the mixture was filtered and the solventevaporated. Kugelrohr distillation (130° C., 0.5 mmHg) gave the productas a brown solid.

m.p. 88-92° C. (Found: C, 78.5; H, 7.3; N, 14.0 Calc. for C₁₃ H₁₄ N₂ ;C, 78.75; H, 7.1; N, 14.1%). δH [250 MHz; (CD₃)₂ CO] 1.85 (2H, quin,J=6.8, CH₂ -4), 2.27 (3H, s, CH₃), 2.50 (4H, t, J=6.8, CH₂ -3, CH-₂ -5),7.05-7.23 (4H, m, Ph--H), 7.55 (1H , s, NH), νmax (KBr)/cm⁻¹ 13285(N--H), 3030 (Ar--H), 2928, 2877 (C--H), 2187 (CN), 1626 (Ar).

EXAMPLE 41 9-Amino-5-methyl-2.3-dihydro-1H -cyclopenta[1,2-b] quinoline(21)

2-(2'-methylphenyl)-aminocyclopent-1-ene-carbonitrile (Example 40) (2.0g, 10.1 mmol) and titanium tetrachloride (1.2 ml, 11.0 mmol) were heatedtogether at 140° C. for 1 hour, under nitrogen. After cooling,10M-sodium hydroxide (20 ml) was added. The mixture was heated underreflux for 1 hour. The product was extracted into dichloromethane, dried(Na₂ SO₄) filtered and the solvent evaporated. Kugelrohr distillation(195° C., 0.15 mmHg) gave the product as yellow crystals.

m.p. 198-200° C. (Found: C, 79.0; H, 7.0; N, 14.0. C₁₃ H₁₄ N₂ requiresthat C, 78.75; H, 7.1; N, 14.1%). δH [250 MHz; (CD₃)₂ SO] 2.05 (2H,quin, J=7.4, CH₂ -2), 2.58 (3H, s, CH₃), 2.81 (2H, t, J=7.3, CH₂ -1),2.91 (2H, t, J=7.6, CH₂ -3), 6.33 (2H, s, NH₂), 7.17 (1H , t, J=7.6,Ar--H-7), 7.35 (1H, d, J=6.5, Ar--H-6), 7.95 (1H, d, J=8.3, Ar--H-8),νmax (KBr)/cm⁻¹ 3489 (N--H). 3183 (Ar--H), 2953 (c--H), 1677 (Ar).

EXAMPLE 42 2-(4-Methylphenyl)-aminocyclopent-1-ene-carbonitrile

4-Methylaniline (Aldrich Chemicals) (92.2 g, 20.6 mmol),2-oxocyclopentanecarbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under refluxfor 16 hours. After cooling, the mixture was filtered and the solventevaporated. Kugelrohr distillation (125° C., 0.06 mmHg) gave the productas a brown solid.

m.p. 110-112° C. (Found: C, 77.7; H, 7.3; N, 13.7 Calc. for C₁₃ H₁₄ N₂C, 78.75; H, 7.1; N, 14.1%). δ_(H) [250 MHz; (CD₃)₂ SO] 1.91 (2H, quin,J=7.4, CH₂ -4), 2.27 (3H, s, CH₃), 2.52 (2H, t, J=5.7, CH₂ -3), 2.65(2H, t, J=7.1, CH₂ -5), 7.04-7.14 (4H, m, Ph--H), 7.95 (1H , s, NH),νmax (KBr)/cm⁻¹ 3311 (N--H), 3106, 3030 (Ar--H), 2279, 2877 (C--H), 2187(CN), 1651 (Ar).

EXAMPLE 43 9-Amino-7-methyl-2,3-dihydro-1H-cyclopenta [1,2-b] quinoline(24)

2-(4'-Methylphenyl)-aminocyclopent-1-ene-carbonitrile (Example 42) (2.0g, 10.1 mmol) and titanium tetrachloride (1.2 ml, 11.0 mmol) were heatedtogether at 140° C. for 1 hour, under nitrogen. After cooling,10M-sodium hydroxide (20 ml) was added. The mixture was heated underreflux for 1 hour. The product was extracted into dichloromethane, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(180° C., 0.1 mmHg) gave the product as yellow crystals.

m.p. 200-202° C. (Found: C, 78.8; H. 7.2; N. 13.9 C₁₃ H₁₄ N₂ requiresthat C, 78.75; H, 7.1; N, 14.1%). δH [250 MHz; (CD₃)₂ SO] 2.03 (2H,quin, J=7.5, CH₂ -2) , 2.43 (3H, s, CH₃), 2.79 (2H, t, J=7.4, CH₂ -1),2.86 (2H, t, J=7.6, CH₂ -3), 6.29 (2H, s, NH₂), 7.32 (1H, dd, J=8.5 and1.5, Ar--H-6) , 7.56 (1H, d, J=8.5, Ar--H-5), 7.90 (1H, s, Ar--H-8).νmax (KBr)/cm⁻¹ 3489, 3438 (N--H), 3157 (Ar--H), 2928, 2851 (C--H), 1677(Ar).

EXAMPLE 44 2-(2',5'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile

2,5-Dimethylaniline (Avocado) (2.4 g, 19.8 mmol),2-oxocyclopentanecarbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were added under refluxfor 17 hours. After cooling, the mixture was filtered and the solventevaporated. Kugelrohr distillation (125° C., 0.08 mmHg) gave a brown oilwhich slowly crystallised over time.

m.p. 105-107° C. (Found: C, 78.6; H, 7.5; N, 12.8 C₁₄ H₁₆ N₂ requiresthat C, 79.2; H, 7.6; N, 13.2%). δH [250 MHz; (CD₃)₂ CO] 1.89 (2H, quin,J=7.4, CH₂ -4), 2.22 (3H, s, CH₃), 2.27 (3H, s, CH₃), 2.53 (4H, m,CH,-5, CH₂ -3), 6.92 (1H, d, J=7.5, Ar--H-4), 6.98 (1H , s, Ar--H-6),7.08 (1H, d, J=7.8, Ar--H-3), 7.51 (1H , s, NH). νmax (KBr)/cm⁻¹ 3285(N--H), 3055 (Ar--H), 2979, 2928 (C--H), 2187 (CN), 1651 (AR).

EXAMPLE 45 9-Amino-5,8-dimethyl-2,3-dihydro-1H -cyclopenta [1,2-b]quinoline (20)

2-(2',5'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile (Example 44)(2.1 g, 9.7 mmol) and titanium tetrachloride (1.2 ml, 11.0 mmol) wereheated together at 140° C. for 1 hour, under nitrogen. After cooling,10M-sodium hydroxide (20 ml) was added. The mixture was heated underreflux for 1 hour. The product was extracted into dichloromethane, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(160° C., 0.15 mmHg) gave the product as a yellow oil which slowlycrystallised over time.

m.p. 95-97° C. (Found: C, 74.9; H, 8.0; N, 12.6 C₁₄ H₁₁ N₂ requires thatC, 79.2; H, 7.6; N, 13.2%). δH [250 MHz; CDCl₃ ] 2.19 (2H, quin, J=7.6,CH₂ -2), 2.67 (3H, s, CH₃), 2.80 (2H, t, J=6.8, CH₂ -1), 2.91 (3H, s,CH₃) , 3.11 (2H, t, J=7.5, CH-3), 4.73 (2H, s, NH₂), 6.95 (1H , d,J=5.0, Ph--H), 7.25 (1H, d, J=7.5, Ph--H). νmax (KBr)/cm⁻¹ 3489, 3462(N--H), 3260 (Ar--H), 2928, 2851 (C--H), 1651 (Ar).

EXAMPLE 46 2-(2',4'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile

2,4-Dimethylaniline (Fluka) (2.4 g, 19.8 mmol),2-oxocyclopentanecarbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under refluxfor 17 hours. After cooling, the mixture was filtered and the solventevaporated. Kugelrohr distillation (150° C., 0.1 mmHg) gave the productas a brown solid.

m.p. 113-116° C. (Found: C, 78.8; H, 7.9; N, 12.7 C₁₄ H₁₆ N₂ requiresthat C, 79.2; H, 7.6; N, 13.2%). δH [250 MHz; (CD₃)₂ CO] 1.88 (2H, quin,J=7.4, CH₂ -4), 2.24 (3H, s, CH₃), 2.27 (3H, s, CH₃), 2.51 (4H, m, CH₂-5, CH₂ -3), 6.95-7.05 (3H, m, Ph--H), 7.46 (1H , s, NH). νmax(KBr)/cm⁻¹ 3259 (N--H), 3055 (Ar--H), 2979, 2928 (C--H), 2187 (CN), 1626(Ar).

EXAMPLE 47 9-Amino-5-7-Dimethyl-2,3-dihydro-1H-cyclopenta [1,2-b]quinoline (23)

2-(2',4'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile (Example 46)(2.0 g, 9.4 mmol) and titanium tetrachloride (1.2 ml, 11.0 mmol) wereheated together at 140° C. for 1 hour, under nitrogen. After cooling,10M-sodium hydroxide (20 ml) was added. The mixture was heated underreflux for 1 hour. The product was extracted into dichloromethane, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(160° C,, 0.01 mmHg) gave the product as a pale yellow solid.

m.p. 211-213° C. (Found: C, 79.1; H, 7.4; N, 12.9 C₁₄ H₁₆ N₂ requiresthat C, 79.2; H, 7.6; N, 13.2%). δH [250 MHz; (CD₃)₂ SO] 2.03 (2H, quin,J=7.5, CH₂ -2), 2.39 (3H, s, CH₃), 2.54 (3H, s, CH₃), 2.79 (2H, t,J=7.3, CH₂ -1), 2.88 (2H, t, J=7.6, CH₂ -3), 6.22 (2H, s, NH₂), 7.20(1H, s, Ph--H), 7.73 (1H , s, Ph--H). νmax (KBr)/cm⁻¹ 3489, 3438 (N--H),3209 (Ar--H), 2979, 2928, (C--H) 1651 (Ar)

EXAMPLE 48 2-(2',3'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile

2,3-Dimethylaniline (Aldrich) (2.4 g, 19.8 mmol),2-oxocyclopentanecarbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under refluxfor 17 hours. After cooling, the mixture was filtered and the solventevaporated. Kugelrohr distillation (140° C., 0.06 mmHg) gave the productas a yellow solid.

m.p. 100-103° C. (Found: C, 79.0; H, 7.9; N, 13.1 C₁₄ H₁₆ N₂ requires C,79.2; H, 7.6; N, 13.2%). δH [250 MHz; (CDCl₃ ] 1.92 (2H, quin, J=7.3,CH₂ -4), 2.19 (3H, s, CH₃), 2.31 (3H, s, CH₃), 2.46 (2H, t, J=7.5, CH₂-3), 2.60 (2H, t, J=7.1, CH₂ -5), 6.17 (2H, s, NH₂), 6.93-7.17 (3H, m,Ph--H). νmax (KBr)/cm⁻¹ 3311 (N--H), 3080 (Ar--H), 2928, 2877 (C--H),2187 (CN), 1651 (Ar)

EXAMPLE 49 9-Amino-5,6-dimethyl-2,3-dihydro-1H-cyclopenta [1,2-b]quinoline (26)

2-(2',3'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile (Example 48)(1.2 g, 5.8 mmol) and titanium tetrachloride (0.7 ml, 5.8 mmol) wereheated together at 140° C. for 1 hour, under nitrogen. After cooling,10M-sodium hydroxide (20 ml) was added. The mixture was heated underreflux for 1 hour. The product was extracted into dichloromethane, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(160° C., 0.06 mmHg) gave the product as yellow crystals.

m.p. 215-216° C. (Found: C, 79.3; H, 8.0; N, 11.9 C₁₄ H₁₆ N₂ requires C,79.2; 7.6; N, 13.2%). δH [250 MHz; (CD₃)₂ SO] 2.04 (2H, quin, J=7.6, CH₂-2), 2.37 (3H, s, CH₃), 2.54 (3H, s, CH₃), 2.79 (2H, t, J=7.3, CH₂ -1),2.90 (2H, t, J=7.8, CH₂ -3), 6.26 (2H, s, NH₂), 7.11 (1H , d, J=8.5,Ph--H), 7.85 (1H , d, J=8.5, Ph--H). νmax (KBr)/cm⁻¹ 3489, 3438 (N--H),3183 (Ar--H), 2928 (C--H), 1651 (Ar).

EXAMPLE 50 2-(3',5'-Dimethylphenyl)-aminocyclopent-1-ene-carbonitrile

3,5-Dimethylaniline (Aldrich Chemicals) (2.4 g, 19.8 mmol),2-oxocyclopentanecarbonitrile (Example 11) (2.2 g, 20.2 mmol), calciumchloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under refluxfor 18 hours. After cooling, the mixture was filtered and the solventevaporated. Kugelrohr distillation (150° C., 0.3 mmHg) gave the productas a yellow solid.

m.p. 150-151° C. (Found: C, 79.2; H, 7.6; N, 13.2 C₁₄ H₁₆ N₂ requiresthat C, 79.2; H, 7.6; N, 13.2%). δH [250 MHz; (CD₃)₂ SO] 1.92 (2H, quin,J=7.3, CH₂ -4), 2.25 (6H, s, CH₃, CH₃), 2.53 (2H, td, J=8.5 and 1.3, CH₂-3), 2.68 (2H, t, J=7.5, CH₂ -5), 6.70 (1H , s, Ar--H-4), 6.78 (2H, s,Ar--H-2, Ar--H-6), 7.90 (1H, s, NH). νmax (KBr)/cm⁻¹ 3285 (N--H),3030(Ar--H), 2928, 2877 (C--H), 2187 (CN), 1651 (Ar).

EXAMPLE 51 9-Amino-6,8-dimethyl-2,3-Dihydro-1H -cyclopenta [1,2-b]quinoline (30)

2-(3',5'-Dimethylphenyl) aminocyclopent-1-ene-carbonitrile (Example 50)(1.5 g, 7.1 mmol) and titanium tetrachloride (1.2 ml, 11.0 mmol) wereheated together at 140° C. for 1 hour, under nitrogen. After cooling,10M-sodium hydroxide (20 ml) was added. The mixture was heated underreflux for 1 hour. The product was extracted into dichloromethane, dried(Na₂ SO₄), filtered and the solvent evaporated. Kugelrohr distillation(180° C., 0.3 mmHg) gave the product as a white solid.

m.p. 132-135° C. δH [250 MHz; (CD₃)₂ SO] 2.03 (2H, quin, J=7.6, CH₂ -2),2.32 (3H, s, CH₃), 2.77 (2H, t, J=7.5, CH₂ -1), 2.85 (2H, t, J=7.9, CH₂-3), 2.84 (3H, s, CH₃), 5.74 (2H, s, NH₂), 6.86 (1H , s, Ph--H), 7.29(1H , s, Ph--H). νmax (KBr)/cm⁻¹ 3489, 3438 (N--H), 3030 (Ar--H), 2953,2877 (C--H), 1651 (Ar).

EXAMPLE 52 9-Amino-2,3-dihydro-[1H ]-cyclopenta-[b]-quinoline (29)

Anthranilonitrile (5.0 g, 42.3 mmol), cyclopentanone (4.1 g, 46.7 mmol),boron trifluoride diethyl etherate (1M, 10 ml, 81.8mmol) were treatedaccording to the general procedure to give the title compound.

Recrystallised: m.p. 180-182° C. (aq. EtOH) (lit. 183-183.5° C.)^(R).Found: C, 78.15; H, 6.5; N, 14.95. Calculated for C₁₂ H₁₂ N₂ : C, 78.35;H, 6.55; N, 15.2%. δH (250 MHz, CDCl₃) 2.19 (2H, quintet, J=7.6, CH₂),2.88 (2H, t, J=7.5, CH₂), 3.10 (2H, t, J=7.8, CH₂), 4.65 (2H br s,exchanges with D₂ O, NH₂), 7.33 (1H, t, J=8.05, aryl-H) , 7.57 (1H, t,J=8.11, aryl-H), 7.71 (1H, d, J=8.3, aryl-H), 7.89 (1H , d, J=8.4,aryl-H).

Maleate salt

m.p. 100-105° C. Found: C, 63.9; H, 5.3; N, 9.3. Calculated for C₁₂ H₁₂N₂.C₄ H₄ O₄ : C, 64.0; H, 5.4; N, 9.3%. δH(250 MHz, CD₃ OD) 2.34 (2H,quintet, J=7.8, CH₂), 2.97 (2H, t, J=7.1, CH₂), 3.23 (2H, t, J=7.8,CH₂), 6.23 (2H, s, maleate), 7.61 (1H, td, J=6.9, 1.3, aryl-H), 7.35(1H, d, J=8.5, aryl-H), 7.86 (1H, td, J=6.9, 1.2, aryl-H), 8.23 (1H; dd,J=8.5, 0.7, aryl-H).

EXAMPLE 53 9-Amino-5-hydroxy-2,3-dihydro-1H-cyclopenta [b] quinoline(12)

Under nitrogen, titanium tetrachloride (3.46 g, 18.2 mmol) was added to2-(2'-methoxyphenyl) aminocyclopent-1-ene (3.4 g, 15.9 mmol) and thestirred mixture was heated at 140° C. for 1 hour. After cooling,10M-sodium hydroxy solution (20 cm³) was added and the mixture heatedunder reflux for 1 hour. After being allowed to cool, the mixture wasfiltered and the solids washed with dichloromethane. Any organics in thefiltrate were also soxhlet extracted into dichloromethane. All extractswere combined, dried (Na₂ SO₄), filtered and the solvent evaporated.Purification by recrystallisation (ethanol) and Kugelrohr distillationgave the title compound as an off-white powder.

m.p. 187-188° C. Found: C, 71.75; H, 6.08; N, 13.73%. C₁₂ H₁₂ N₂ Orequires: C, 71.98; H, 6.04; N, 13.99%. νmax (KBr)/cm⁻¹ 3566, 3438 (N--Hstr), 3438 (OH str), 2928 (C--H str), 1651-1498 (C═C str). δ_(H) [250MHz; (CD₃)₂ SO] 2.07 (2H, quin, J=7.5, CH₂ -2), 2.81 (2H, t, J=7.3, CH₂-1), 2.94 (2H, t, J=7.6, CH₂ -3), 4.36 (1H , br s, OH), 6.47 (2H, s,NH₂), 6.86 (1H , d, J=7.4, Ar--H-6), 7.13 (1H, t, J=7.9, Ar--H-7), 7.54(1H , d, J=8.3, Ar--H-8). m/z 200.0953 (M⁺, 100%), 199.0878 (M⁺ --H,30%) [theory m/z 200.0949, 199.0871].

EXAMPLE 54 Pharmacology

Four assays were employed to measure biological activity:

Inhibition of Acetylcholinesterase uptake activity (AChE)

Inhibition of Butyrylcholinesterase activity (BChE)

Inhibition of 5-HT (serotonin) uptake

Inhibition of noradrenaline uptake (NA).

The details of the assays employed are the same as for those outlined inExamples 8(A) to 8(C) inclusive, except that the drugs tested andresults are as shown in Tables 2 and 3.

As in Example 8, the biological activity of primary interest was that ofAChE and 5-HT uptake. BChE uptake was measured such that compoundsselective for AChE could be located. Inhibition of noradrenaline uptakewas measured since compounds having the ability to potentiatetransmission involving noradrenaline as well as 5-HT and acetylcholineare of interest.

                  TABLE 2                                                         ______________________________________                                                   AChE     TACRINE   BChE   TACRINE                                  COMPOUND   IC50 #μM                                                                            RATIO     IC50 #μM                                                                          RATIO                                    ______________________________________                                        TACRINE    0.078    1.000     0.025  1.00                                      8         0.035    2.229     10.000 0.003                                     9         0.120    0.650     1.400  0.018                                    10         0.410    0.190     15.000 0.002                                    11         0.120    0.650     0.750  0.033                                    12         1.000    0.078     0.500  0.050                                    13         0.290    0.269     0.270  0.093                                    14         0.078    1.000     1.510  0.017                                    15         0.064    1.219     0.041  0.610                                    16         0.140    0.557     0.530  0.047                                    17         0.010    8.041     0.13   0.19                                     18         0.200    0.390     0.410  0.061                                    19         1.300    0.060     1.32   0.019                                    20         1.900    0.041     1.400  0.018                                    21         3.300    0.024     13.800 0.002                                    22         3.500    0.022     14.500 0.002                                    23         19.000   0.004     52.000 0.000                                    24         6.700    0.012     1.100  0.023                                    25         10.000   0.008     1.900  0.013                                    26         11.600   0.007     9.200  0.003                                    27         18.000   0.004     NB     XXXXX                                    28         39.600   0.002     13.800 0.002                                    29         0.056    1.393     0.052  0.481                                    30         0.130    0.600     0.710  0.035                                    31         0.470    0.166     4.800  0.005                                    32         0.540    0.144     8.800  0.003                                    33         36       0.002     N/A    N/A                                      34         2.900    0.030     N/A    N/A                                      35         >100     N/A       N/A    N/A                                      36         47.000   0.002     N/A    N/A                                      ______________________________________                                         NA = NOT ATTEMPTED                                                            NB = No Block at 100 μM.                                              

                  TABLE 3                                                         ______________________________________                                                 5-HT UPTAKE         NA UPTAKE                                                 INHIBITION TACRINE  INHIBITION                                                                             TACRINE                                 COMPOUND #μM     RATIO    #μM   RATIO                                   ______________________________________                                        TACRINE  7.600      1.000    6.700    1.000                                    8       2.000      3.800    NA       NA                                       9       52.000     0.146    NA       NA                                      10       260.000    0.029    NA       NA                                      11       3.700      2.054    12.000   0.558                                   12       14.500     0.524    0.700    9.571                                   13       42.000     0.181    0.700    9.571                                   14       43.000     0.177    3.300    2.030                                   15       22.000     0.345    0.700    9.571                                   16       39.000     0.195    0.002    3350.000                                17       1.500      5.067    NA       NA                                      18       2.300      3.304    NA       NA                                      19       7.000      1.086    2.700    2.481                                   20       3.900      1.949    NA       NA                                      21       12.000     0.633    NA       NA                                      22       104.000    0.073    3.100    2.161                                   23       7.900      0.962    NA       NA                                      24       17.000     0.447    NA       NA                                      25       5.300      1.434    NA       NA                                      26       4.400      1.727    NA       NA                                      27       3.500      2.171    NA       NA                                      28       5.800      1.310    NA       NA                                      29       21.000     0.362    0.600    11.167                                  30       8.100      0.938    NA       NA                                      33       18.000     0.400    NA       NA                                      34       18.000     0.400    NA       NA                                      35       114.000    0.070    NA       NA                                      36       29.000     0.300    NA       NA                                      ______________________________________                                         NA = Not attempted                                                            NB = No block at 100 μM                                               

What is claimed is:
 1. The compound: ##STR33##
 2. The compound:
 3. Aprocess for preparing a compound according to Formula (11(c)): whereinRis selected from H, F, Cl, Br and OCH₃ ; by(i) condensing a 1-indanonewith an alkyl formate forming a 2-OH methylene indan-1-one; (ii)condensing the 2-OH-methylene indan-1-one with a phenyl hydrazine ofFormula (VIII): ##STR34## wherein R is selected from H, F, Cl, Br, andOCH₃ ; forming an indenopyrazole of Formula (IX): ##STR35## (iii)opening the pyrazole ring and forming a phenyl amino cyano-1-indene ofFormula (X): ##STR36## followed by Lewis base catalysis.
 4. A processfor preparing a compound of Formula (III) comprising(i) condensing acyclic a-cyanoketone of Formula (XI) ##STR37## wherein X represents--(CH₂)-- and n is a whole integer selected from 1 and 2; and J is a 6carbon-membered unsubstituted ring optionally fused to Ring C at anyface of Ring C with the proviso that the said 6 carbon-memberedunsubstituted ring is fused at a face which does not extend from thecyano or ketone substituted carbon of Ring C; with an aniline derivativeof Formula (XII): ##STR38## wherein R¹ is selected from H, NH₂, OH, F,Cl, Br, I, OCH₃, C₁ -C₆ alkyl and aryl (phenyl); R² is selected from H,C₁ -C₆ alkyl, C₁ -C₆ alkoxy, Cl, Br, F, I and OH; R³ is selected from H,F, Cl, Br, I, OH, OCH₃, and C₁ -C₆ alkyl; R⁴ is selected from H, F, Cl,Br, I, OCH₃, OH, and C₁ -C₆ alkyl; and (ii) cyclising the condensationproduct of step (i) using a Lewis acid.
 5. A process according to claim4 wherein the α cyanoketone of Formula (XI) is ##STR39## wherein Xrepresents --(CH₂)-- and n is a whole integer selected from 1 and 2; andthe aniline derivative of Formula (XII) is ##STR40## wherein R¹, R², R³and R⁴ are independently selected from H, Br, Cl, OH, CH₃ and OCH₃ . 6.A process according to claim 4 wherein R¹, R², R³ and R⁴ of the anilinederivative of Formula (XII) are independently selected from H, F, Cl andOH.
 7. A method for the treatment of Alzheimer's disease in a patientwhich comprises administering to the patient a clinically useful amountof at least a compound of Formula 11(c) ##STR41## wherein R is selectedfrom H, F, Cl, Br and OCH₃, or a pharmaceutically acceptable saltthereof.
 8. A method according to claim 7 wherein the compound isadministered in association with a pharmaceutically acceptable carrier.9. A method for the treatment of Alzheimer's disease in a patient whichcomprises administering to the patient a clinically useful amount of atleast a compound of Formula (II (d)): ##STR42## or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier.
 10. A pharmaceutical formulation comprising a compound ofFormula (II (d)): ##STR43## or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable carrier.